Julia C. Colwell1,2
Marina E. Emborg1,2,3*- 1Preclinical Parkinson’s Research Program, Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, United States
- 2Cellular and Molecular Pathology Graduate Program, University of Wisconsin, Madison, WI, United States
- 3Department of Medical Physics, University of Wisconsin, Madison, WI, United States
Tauopathies are neurodegenerative disorders characterized by the abnormal accumulation and aggregation of hyperphosphorylated tau protein. They can be primary or secondary depending on whether tau inclusions are the predominant pathology (e.g.: frontotemporal dementia related to tau) or are found with other proteinopathies (e.g.: Alzheimer’s disease), respectively. Currently, there are no effective treatments to prevent or slow down progressive tau accumulation. Animal models play a critical role in the efforts to unravel the mechanisms leading to tauopathies and identifying therapeutic targets. Nonhuman primates (NHPs) present several advantages for the study of tauopathies, as they have complex neuroanatomy and behavior that resembles human traits, and their tau gene and protein are highly conserved. Moreover, aged NHPs, like humans, can present various tau inclusions in their brains, although whether NHPs can develop human-like tau-related neurodegenerative disorders is currently debated. The main goal of this review is to analyze available reports on tau pathologies and models of tauopathies in NHPs considering the complexity of the tau protein and associated tau pathologies. Here, we first summarize current available information on human and NHP tau under physiological conditions in order to highlight species differences and gaps in knowledge. We then analyze reports on tau pathologies in aged NHPs compared to human aging and tauopathy, followed by an evaluation of current and emerging NHP models of tauopathy. Lastly, we discuss the practical and ethical challenges of doing tauopathy research in NHPs, and how to best leverage it to ultimately find solutions for patients with these disorders.
1 Introduction
Tau was first described in 1975 as a protein factor essential for self-assembly of tubulin dimers into microtubules (Weingarten et al., 1975). Today, tau is a notable member of the microtubule-associated protein (MAP) family (Dehmelt and Halpain, 2005). In the healthy adult central nervous system (CNS), tau is primarily associated to neuronal axons where it provides microtubule stability and regulates motor and vesicle transport (Lee and Leugers, 2012). Tau is mainly recognized for its role in neurodegenerative disorders termed “tauopathies,” in which hyperphosphorylated tau forms intracellular inclusions. While all tauopathies are defined by abnormal accumulation of phosphorylated tau (p-tau) and progressive neurological dysfunction, each disorder displays variations in clinical presentation, pathological tau conformation, and spatial–temporal tau accumulation. Tauopathies are classified as primary or secondary, depending on whether tau pathologies are the predominant features or they are present with other pathologies. Examples of primary tauopathies include sporadic and genetic forms of frontotemporal dementia (FTD) related to tau. Alzheimer’s disease (AD) is considered a secondary tauopathy, as beta amyloid (Aβ) plaque deposition precedes tau accumulation (Cody et al., 2024). Today, there are no effective treatments to prevent or slow down progressive p-tau accumulation.
Different animal models of tauopathies have been developed, including genetically modified rodents, fruit flies, worms, and zebrafish expressing gene mutations associated to tau pathology in humans (Dujardin et al., 2015). These models help to unravel tau-related mechanisms of disease, identify therapeutic targets, and evaluate novel therapies. Nonhuman primates (NHPs) have several species-specific advantages for the study of tauopathies. NHPs have complex neuroanatomy, including a cingulate gyrus with greater size caudally than rostrally and a reduced olfactory lobe and bulb (Gonzales et al., 2015). An enlarged frontal lobe allows NHPs to perform higher order executive functioning, which facilitates assessment of attention, learning, and memory (Phillips et al., 2014). Crucially, the microtubule-associated protein tau (MAPT) gene encoding for tau and the tau protein sequence are highly conserved between humans and NHPs, with increasing differences across the phylogenetic tree. Moreover, various tau inclusions can be present in the brain of aged NHPs, similar to aged humans (Walker and Jucker, 2017), although whether NHPs can develop human-like tau-related neurodegenerative disorders is currently debated.
The main goal of this review is to analyze available reports on tau pathologies and models of tauopathies in NHPs considering the complexity of the tau protein and associated tau pathologies. Here, we first summarize current available information on human and NHP tau under physiological conditions in order to highlight species differences and gaps in knowledge. We then analyze reports on tau pathologies in aged NHPs compared to human aging and tauopathy, followed by an evaluation of current and emerging NHP models of tauopathy. Lastly, we discuss the practical and ethical challenges of doing tauopathy research in NHPs, and how to best leverage it to ultimately find solutions for patients with these disorders.
2 MAPT gene and tau protein structure and function
In humans the MAPT gene is located on chromosome 17q21.1 and has two haplotypes, H1 and H2, which represent a ~1 MB inversion of one another (Zody et al., 2008). H1 homozygosity is more common in the human population and is associated with an increased risk for tauopathies, whereas H2 homozygosity seems to be neuroprotective (Wade-Martins, 2012).
MAPT contains 16 exons, of which 8 are constitutively expressed (exons 1, 4, 5, 7, 9, 11, 12, and 13) (Figure 1A). Exons 2, 3, 4a, 6, 8, and 10 are subject to alternative splicing, and exons 0 and 14 are transcribed but not translated (Andreadis, 2005). The tau protein has four distinct regions: (1) the N-terminal projection domain, encoded by exons 1–3; (2) the proline rich region (PRR), encoded by exons 4–8; (3) the microtubule binding repeat (MTBR) region, encoded by exons 9–12; and (4) the C-terminal domain, encoded by exon 13. The human CNS expresses six distinct tau isoforms, depending on the combination of exons transcribed (Figure 1B). The isoforms differ by the number of N-terminal inserts and microtubule binding repeats (MTBR). Isoforms may contain zero (0 N), one (1 N), or two (2 N) N-terminal inserts; exons 2 and 3 encode 1 N and 2 N isoforms, respectively. Tau may contain either three (3R) or four (4R) MTBRs, differentiated by the inclusion of exon 10 (Andreadis, 2005; Andreadis, 2013).
Figure 1. Tau protein in human and nonhuman primate species. (A) Tau has four distinct regions: (1) the N-terminal projection domain (blue outline), (2) the proline-rich region (orange outline), (3) the microtubule binding domain (purple outline), and (4) the C-terminus (yellow outline). Colored boxes represent constitutively expressed exons; empty boxes are exons subject to alternative splicing that translate into (B) the six CNS isoforms of the tau protein. Expression of exons 4a, 6, and 8 is restricted to the human PNS and retina. (C) The longest CNS tau isoform in primates is the 2N4R tau. Black ticks in the protein region identifies amino acid (aa) variations in 2N4R tau in each nonhuman primate species compared to the human sequence. Common marmosets, squirrel monkeys, and gray mouse lemur tau has aa deletions, indicated by dashed black lines through the exons in which they occur. Gray mouse lemurs have an aa addition in exon 2, denoted by a solid black line through the exon. Created in https://BioRender.com.
The four regions of the tau protein direct its activity. N-terminal projection carries a negative charge which is repelled by the negatively charged tubulin surface. It contributes to the spatial organization of tau by extending out from the microtubule surface and interacting with the axonal plasma membrane (Amos, 2004; McKibben and Rhoades, 2019). Expression of exons 2 and 3 can negatively regulate microtubule binding through interactions with the PRR flanking the N-terminus immediately downstream. The PRR carries a net positive charge and can independently promote tubulin polymerization and enhance the microtubule binding ability of the MTBR (McKibben and Rhoades, 2019). The MTBR can have up to four 31–32 amino acid-long repeats, denoted as R1, R2, R3, and R4, respectively (Mandelkow et al., 2007). The MTBRs interact with the microtubule surface through weak van der Waals interactions and highly shielded ionic forces, and the inclusion of exon 10 (R2) strengthens this interaction (Goode and Feinstein, 1994). The C-terminus helps stabilize tau and prevent aggregation (Geng et al., 2015).
Tau protein expression changes across the human lifespan. In the fetal human CNS, all tau isoforms are 0N3R (Andreadis, 2005). Exon 10 inclusion increases dramatically during the perinatal period and persists throughout childhood and adult life. Exon 2 inclusion stably increases from the perinatal period until approximately 10 years of age, at which its expression plateaus. Exon 3 inclusion slightly increases from fetal to adult stages but remains at lower levels than exons 2 and 10 (Hefti et al., 2018; Takuma et al., 2003). Healthy adult human brains express 3R and 4R isoforms in an approximate 1:1 ratio. 0 N, 1 N, and 2 N isoforms comprise ~9%, ~37%, and ~54% of all adult CNS tau isoforms, respectively (Liu and Gong, 2008). Differences in MAPT splicing are minimal across neuroanatomical regions throughout the human lifespan (Hefti et al., 2018).
The few studies assessing expression of tau proteins across brain regions have focused on areas typically affected by AD. Total tau expression seems to be most abundant in the hippocampus and cortical gray matter (Paterno et al., 2022; Trojanowski et al., 1989). Tau truncated at the N- and C-terminus, which has been proposed to increase tau aggregation in AD (Gu et al., 2020), was found in the hippocampus, entorhinal, prefrontal, and motor cortices in adults ranging in age from 18–104 years, with more widespread C-terminal than N-terminal truncation. Notably, an age-dependent loss of full sequence tau associated to C-terminal truncation was observed in the entorhinal cortex, particularly in individuals aged >60 years (Friedrich et al., 2021).
Physiological tau is heat- and acid-stable, highly soluble, and lacks a higher order structure; thus, it is considered an intrinsically disordered protein (Mandelkow et al., 2007). Over half of the primary sequence is comprised of the amino acids Glycine (Gly), Lysine (Lys), Proline (Pro), Serine (Ser), and Threonine (Thr) residues, all of which except Thr are disorder-promoting (Mandelkow et al., 2007; Uversky, 2019). This primary structure elicits an extended, “random coil” secondary structure with little evidence for α-helices and β-sheets (Avila et al., 2016). Even when bound to tubulin, tau retains an extended structure, with its MTBR domain spanning three tubulin monomers across the longitudinal interface of a protofilament. Tau can remain associated to αβ tubulin dimers over repeated cycles of protofilament assembly and disassembly because it binds in a hydrophobic pocket at the αβ tubulin dimer interface, a region that is structurally unaltered by GTP hydrolysis during microtubule polymerization (Kadavath et al., 2015; Kellogg et al., 2018). Unbound, soluble, monomeric tau adopts a “hairpin” structure in which the N- and C-terminus fold over the MTBR, which is thought to prevent aggregation (Chen D. et al., 2019; Mirbaha et al., 2018).
Post-translational modifications of tau include phosphorylation, acetylation, ubiquitination, methylation, and glycation (Alquezar et al., 2020). These changes contribute to tau function and homeostasis by modulating its catabolism, localization, structure, and interactions with other proteins; they also play a role toward the generation of pathological tau (Binder et al., 2005). Phosphorylation is one of the most common post-translational modifications of tau; it is also one of the most studied, as pathological tau aggregates are known to be hyperphosphorylated. Approximately 20% of tau residues can become phosphorylated (Stoothoff and Johnson, 2005) (Table 1), and the extended structure of tau leaves it prone to such post-translational modification. Most phosphorylation occurs in the PRR or C-terminus immediately downstream of the MTBRs (Kimura et al., 2014). Phosphorylated epitopes can be recognized by several antibodies (Table 2). Tightly regulated phosphorylation and dephosphorylation is thought to control tau-microtubule interactions and is carried out by a repertoire of kinases (Martin et al., 2013). Generally, phosphorylation in or near the MTBR is thought to decrease tau affinity for tubulin due to the addition of a negative phosphate group near the negatively charged MTBRs (Xia et al., 2021). For example, phosphorylated Ser214 and Ser262 have been shown to promote tau detachment from microtubules (Schneider et al., 1999; Sengupta et al., 1998), although these phosphoresidues are also proposed to be neuroprotective, potentially due to a conformation change in the tau protein (Augustinack et al., 2002; Schneider et al., 1999).
Table 1. List of potential and reported tau phosphorylation sites in the brain of healthy humans, healthy rhesus macaques, and human Alzheimer’s disease (AD) patients.
Table 2. List of antibodies and their corresponding target epitopes utilized for histological evaluation of tau and phosphorylated tau reported in the reviewed studies of aged NHPs and NHP models of tauopathy.
3 Tau is highly conserved across primate species
In NHPs, the MAPT gene contains the same 16 exons as humans, and the same 8 exons are constitutively expressed. Human and NHP MAPT genes are highly homologous in coding regions, which results in conserved 2N4R tau amino acid sequences among species (Figure 1C).
3.1 Great apes
All great apes, such as gorillas (genus Gorilla), orangutans (genus Pongo), chimpanzees and bonobos (both genus Pan) express the same six CNS tau isoforms as humans (Holzer et al., 2004). The amino acid sequence of the 2N4R tau isoform in the CNS is 100% identical between humans, chimpanzees, and bonobos (Figure 1C). This isoform is 99.5% identical between humans and gorillas differing at H32L and K87E in the N-terminus. Orangutan and human 2N4R tau are less similar, differing at nine amino acids in the N-terminus. In chimpanzees and gorillas, seven of eight single nucleotide polymorphisms that define the MAPT human haplotypes were found to be the H2 sequence (Holzer et al., 2004). Among these two species of great apes, the single nucleotide polymorphisms were conserved and nonpolymorphic (Holzer et al., 2004). A later study demonstrated that both the H1 and H2 haplotypes are present in chimpanzees but probably evolved independently of the human MAPT haplotypes. Unlike humans, the H2 haplotype represents the major allele (~56%) of chimpanzees. In contrast, the investigators found that Sumatran orangutans were H2 homozygotes, while a single Bornean orangutan was H1/H2 heterozygous (Zody et al., 2008).
Intronic sequences regulate exon inclusion, and there is evidence that apes have slight differences in noncoding regions from adult humans, which may lead to differences in tau isoform expression. For example, human MAPT contains a 59- or 60-bp tandem repeat in intron 9 which controls inclusion of exon 10. Human MAPT shares this repeat with gorillas but not always with chimpanzees (Holzer et al., 2004). In an exon trapping experiment, a higher proportion of human and gorilla tau transcripts contained exon 10 than chimpanzees (Holzer et al., 2004). However, on RT-PCR of brain homogenates, chimpanzees and gorillas expressed a higher proportion of exon 10-containing transcripts than humans. Unfortunately, information on tau phosphorylation sites for great apes is not currently available.
3.2 Old World monkeys
Old world monkeys, including rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) macaques express the same six CNS tau isoforms as humans. Macaque 2N4R tau is ~98% identical to human 2N4R tau, differing at 9 amino acids in the N-terminal half of the protein. Macaques share their 2N4R tau sequence with baboons (Papio papio) and African green monkeys (Chlorocebus sabaeous) (Figure 1C). All six tau isoforms are ubiquitously expressed in neurons throughout the rhesus brain (Gambardella et al., 2023). Like great apes, seven of the eight single nucleotide polymorphisms that define the MAPT haplotypes were found to have the H2 sequence in macaques (Holzer et al., 2004). Fluorescent in situ hybridization on chromosomes from three macaque species (M. mulatta, fascicularis, and arctoides) demonstrated H2 homozygosity (Zody et al., 2008).
Exon 8, which has not been reported as transcribed in humans, contains an evolutionarily conserved Pro-Pro-Pro motif that introduces a sharp bend into the protein structure. This bent conformation is proposed to be neuroprotective by sterically hindering aggregation. Furthermore, the inclusion of exon 8 introduces a Tyr residue that is proposed to “hinge” the protein at the interface between the N-terminus and MTBR and, thus, modulate its ability to be phosphorylated at Ser202/Thr205. Interestingly, a study in rhesus macaque brains showed that a proportion of tau mRNAs contain exon 8 (Nelson et al., 1996); tau proteins with exon 8 have not yet been reported.
Several 2N4R tau phosphorylation sites were identified in the prefrontal cortex of five rhesus aged 7–28 years by mass spectrometry (Leslie et al., 2021). It is important to note that potential phosphorylation sites between rhesus and human 2N4R tau are highly conserved. Rhesus tau only has three less potential phosphorylation sites than human tau due to evolutionary differences in amino acid sequence (Figure 1C); these are T52A, T95M, and T220A in the N-terminal half. When tau phosphorylation is compared between cortical tissue from rhesus macaques and healthy humans (Leslie et al., 2021; Xia et al., 2021), several similarities and differences emerge (Table 1). First, the MTBR is the most common site of phosphorylation in both species. Second, rhesus tau has more phosphorylated residues on the N-terminal half of the protein. Lastly, rhesus tau had 16 residues that were phosphorylated in all five animals studied, of which seven residues (i.e., Thr39, Thr50, Ser56, Ser61, Thr69, Ser113, and Thr231) were not phosphorylated in healthy humans. Six of these seven residues occur in the N-terminal half, representing the least conserved portion of the protein. Interestingly, Thr231 is phosphorylated in normal rhesus tau (Gambardella et al., 2023), although this site is described as an early marker of tauopathy in human AD (Augustinack et al., 2002). Age-related increases in pSer235-tau and pSer396-tau, but not pThr181-tau, were identified in rhesus 7–28 years old (Leslie et al., 2021).
3.3 New World monkeys
Tau studies in New World monkeys have focused on common marmosets (Callithrix jacchus) and squirrel monkeys (Saimiri Sciurus). The 2N4R tau isoform of both species is missing a 10 amino acid-long sequence in the N-terminal domain, which was previously referred to as the “primate unique motif” (Stefanoska et al., 2018). Thus, it contains only 431 amino acids, opposed to the 441 amino acid-long 2N4R tau present in humans, apes, and Old World monkeys (Figure 1C). Notably, all other primate suborders still retain this sequence. Adult common marmosets were originally reported to exclusively express 4R isoforms in the CNS, like adult rodents (Sharma et al., 2019). Yet, 3R-tau was recently detected in the brains of marmosets aged 1–10 years, albeit to a lesser extent than 4R-tau (Huhe et al., 2024).
Reports on tau phosphorylation sites in New World monkeys are scarce. Tau in the brain of newborn marmosets is highly phosphorylated at several residues, mirroring human fetal tau and tau phosphorylation in disease (e.g., pSer202/Thr205-tau). In comparison, adult marmosets harbor small amounts of pT231-tau, pS396-tau, and pS404-tau (Sharma et al., 2019).
3.4 Prosimians
Compared to other NHP species, there is limited information on normal tau in prosimians; reports of tau isoform expression and phosphorylation sites are not available. The 2N4R tau isoform in the gray mouse lemur (Microcebus murinus) is 440 amino acids long, with a deletion of a glutamine in the region encoded by exon 7. It has 20 amino acid substitutions in the N-terminal half, as well as a serine addition and lysine deletion in the 1 N insert. There are two amino acid substitutions in the C-terminal half, located in the regions encoded by exons 9 and 13, respectively (Figure 1C).
3.5 What can be learned about the development of tau pathologies through the comparison of tau sequences across primate species?
It is well documented that increasing differences in the tau sequence are observed following the evolutionary scale from humans to great apes, then Old World monkeys, New World monkeys, and finally prosimians. If great apes are protected from neurodegenerative disease, this is likely not explained by tau primary sequence, as 2N4R tau is identical in humans, chimps, and bonobos, and 99.5% similar between humans and gorillas. However, the N-terminus of human tau has an increased amount of disorder compared to tau in Old World monkeys, New World monkeys, and prosimians (Trushina et al., 2019). This understanding could provide a basis for further research in novel protein–protein interactions (e.g., tau interaction with synaptic proteins; Stefanoska et al., 2018). Interestingly, the MTBR is conserved between humans and NHPs, including the VQIINK and VQIVYK hexapeptide motifs, which form the core of the protective “hairpin” structure in normal human tau and the core of PHFs in AD. In NHPs, the relationship between tau sequence and conformation has not been studied; this information could be insightful. Furthermore, studies on neuroanatomical tau abundance and tau fragmentation throughout the lifespan have not been conducted in NHPs and could provide insight on potential disease susceptibility.
Regarding tau isoform expression in NHPs and its relationship to disease susceptibility, there are disparities in data suggesting that humans, chimps, and gorillas may express different levels of exon 10-containing transcripts. A repeat in intron 9 may control the inclusion of exon 10 (Holzer et al., 2004). Further, in adult common marmosets, it has been traditionally reported that 3R isoforms are not expressed (Sharma et al., 2019). However, new research challenges this notion (Huhe et al., 2024). These studies allude to a general need for more research on tau isoform expression across the lifespan in NHPs and the corresponding contributions of intronic elements.
Some phosphoresidues that are considered disease markers in humans (e.g., pT231-tau), have been shown to be expressed in healthy young adult macaques (Gambardella et al., 2023). A thorough investigation of normal tau phosphorylation sites identified by mass spectrometry in any NHP species besides rhesus macaques would help determine relevance of disease-associated phosphorylation sites across species. Moreover, studies encompassing the species’ entire lifespan would help understand age-related changes in p-tau expression compared to disease.
4 The CNS of asymptomatic aged humans can present sporadic tau pathologies
Beyond the changes in tau expression across the lifespan mentioned in section 2, the aged human brain may present intracellular aggregates of hyperphosphorylated tau. These inclusions resemble tau pathologies found in tauopathies, of which neurofibrillary tangles (NFTs) are the most widely recognized (Figure 2A). Detection of NFTs typically relies on their positive staining with silver or with the AT8 antibody targeting the pSer202/pThr205 epitopes (Table 2).
Figure 2. Examples of AT8+ postmortem tau pathologies in human cases of Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), Pick’s disease (PiD), and corticobasal degeneration (CBD). (A) Pretangle (arrowhead) and mature NFT (arrow) in the cornu ammonis (AD). (B) Dystrophic neurites (arrowhead) in the entorhinal cortex (AD). (C) Neuritic plaque (arrow) in the insula (AD). (D) Globose NFT (arrow) in the putamen nucleus (PSP). (E) Pick bodies (arrow) in the cornu ammonis (PiD). (F) Oligodendroglial coiled bodies (arrowheads) in the putamen nucleus (PSP). (G) Thorn-shaped astrocyte (arrow) in the subpial medial temporal lobe (AD). (H) Tufted astrocyte (arrow) in the putamen (PSP). (I) Astrocytic plaque (arrow) in the caudate nucleus (CBD). Scale bar, 100 μm.
Numerous studies of cognitively unimpaired humans (49–105 years old) have reported NFTs in the entorhinal cortex and hippocampus. NFT density is variable between these individuals but is less than that of AD cases (Morris et al., 1991). NFTs have also been reported in brainstem nuclei, the anterior olfactory nucleus, and neocortical areas (Bouras et al., 1993; Nelson et al., 2009; Price et al., 1991), usually to a lesser extent than medial temporal lobe structures.
These publications influenced the establishment of diagnostic criteria for primary age-related tauopathy (PART) (Crary et al., 2014), which refers to elderly subjects that present NFT burden without β-amyloid (Aβ) plaques in the brain at autopsy; NFTs must be Braak stage ≤IV (see section 5.2 for explanation on AD staging). Patients with PART are cognitively unimpaired to mild amnestic, with only few patients exhibiting profound impairments. Crary et al. (2014) note that the overwhelming majority of individuals with PART fall into Braak stage I-II, as Braak stage 0 is uncommon in elderly populations, and Braak stage III/IV without Aβ only occurs in 2–10% of PART cases (Kovacs et al., 2013; Nelson et al., 2009; Schneider et al., 2009). The term was coined to facilitate scientific communication, but it is unclear whether PART is a condition associated with normal aging or is an early indicator of AD or other tauopathies.
5 Human tauopathies
In this section, we present a summary on human tauopathies as a framework for the analysis of reports on tau pathologies in aged NHPs and NHP models of tauopathies. As mentioned in the introduction, tauopathies are neurodegenerative disorders associated to hyperphosphorylated and aggregated tau inclusions in neurons and/or glia. They are classified as primary or secondary depending on whether accumulation of tau pathologies is the main feature. It is important to consider that patients with the same disease diagnosis can have differing clinical presentations, pathological tau conformations, and/or spatial–temporal tau accumulations (Chung et al., 2021). Patients often present mixed pathologies (i.e., tau with alpha-synuclein or TDP-43), which may contribute to syndrome variation, Conditions related to traumatic brain injury, stroke and environmental toxins can also present tau inclusions (Chen and Jiang, 2019; Edwards et al., 2020), but they are beyond the scope of this review.
In addition to mature NFTs, also termed flame-shaped NFTs (Figure 2A), disease-associated tau inclusions include pretangles (Figure 2B), neuritic plaques (Figure 2C), globose NFTs (Figure 2D), Pick bodies (Figure 2E), coiled bodies (Figure 2F), thorn-shaped astrocytes (Figure 2G), tufted astrocytes (Figure 2H), and astrocytic plaques (Figure 2I). All these tau pathologies are visualized by silver staining or AT8 immunohistochemistry. Currently, clinical tauopathy diagnosis is ultimately confirmed by neuropathological evaluation at autopsy.
5.1 Primary tauopathies
All primary tauopathies present pathological tau aggregation, yet they differ on the predominant tau isoform accumulated, affected brain regions, and affected cell type (Chung et al., 2021).
FTD associated with tau accumulation (FTD-tau) is considered a typical primary tauopathy. FTD is the most common form of dementia in patients under 60 years old. It is an umbrella term for disorders presenting with frontal and/or temporal lobe atrophy associated to abnormal accumulation of proteins, such as tau, TDP-43, or FUS (Bang et al., 2015). FTD-tau can be genetic or sporadic; clinical presentations are diverse but fall into three main categories: behavioral variant FTD, progressive primary aphasia, or FTD with amyotrophic lateral sclerosis or parkinsonism (Siuda et al., 2014; Waldö, 2015). Outside of these classifications, progressive cognitive impairment can also be a presenting symptom (Beber and Chaves, 2013). Over 50 mutations in MAPT have been linked to genetic FTD-tau, including MAPT P301S, S320F, and R406W (for review see Strang et al., 2019). Genetic FTD linked to MAPT mutations are denoted FTD associated to chromosome 17 (FTD-17), sometimes termed FTDP-17 if parkinsonism is clinically present (Boeve and Hutton, 2008). Progression and distribution of tau pathologies in FTD varies between FTD subtype and clinical presentation but typically does not follow an AD pattern (Reed et al., 1997). Due to the diversity of neuropathological burden in FTD syndromes, a unified staging system is not possible. Interestingly, an unexpected link between FTD and cerebellar atrophy has recently been discovered (Bocchetta et al., 2016; Bussy et al., 2023; Chen Y. et al., 2019); more research is needed to understand the contribution of different MAPT mutations or sporadic tau pathologies to cerebellar atrophy.
Subtypes of FTD-tau include Pick’s disease (PiD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD); they can be sporadic or genetic. An increased risk for sporadic PiD has been linked to tau haplotype H2; rare mutations or duplications in MAPT have been linked to genetic PiD (Valentino et al., 2024). For PSP, MAPT is the strongest risk locus, with 15 MAPT mutations to date associated with the disease (Wen et al., 2021). With respect to CBD, MAPT mutations are the second most common, after GRN (Arienti et al., 2021). The differential diagnosis between these three diseases is based on clinical presentation and ultimately postmortem neuropathological findings. The pathological hallmark of PiD is the presence of cytoplasmic, round, and exclusively 3R-tau+ inclusions called Pick bodies (Figure 2E). Tau neuropathology in PiD is proposed to originate in the limbic/paralimbic cortices and progress through subcortical regions (Irwin et al., 2016). Neuronal loss predominates in the frontal neocortex, followed by the temporal cortex, parietal cortex, hippocampus, and finally the amygdala (Kovacs, 2015). PSP and CBD are characterized by only 4R-tau+ inclusions. In PSP, globose NFTs (Figure 2D) are found in the basal ganglia, diencephalon, and brainstem nuclei and neuronal loss predominates in the subthalamic nucleus and substantia nigra. Tufted astrocytes (Figure 2H) are found in the precentral gyrus, striatum, and superior colliculus, and occasionally in the thalamus, subthalamic nucleus, red nucleus, and cortex. Oligodendroglial coiled bodies (Figure 2F) are found throughout the white matter. It should be noted that the PSP clinical subtypes have specific patterns of progressive tau accumulation and associated neuronal degeneration and that the non-neuronal cell types affected depend on clinical presentation (Kovacs et al., 2020). In CBD, globose NFTs (Figure 2D) are seen in the substantia nigra and locus coeruleus. Atrophy occurs in the frontal and/or parietal regions with the presence of ballooned neurons; the subthalamic nucleus is typically spared. Astrocytic plaques (Figure 2I) are characteristic of CBD, mainly in the neocortex and striatum. Oligodendroglial coiled bodies (Figure 2F) are also present in the striatum, pallidum, and thalamic fascicle, but usually to a lesser extent than in PSP (Kovacs, 2015; Spina et al., 2019). Importantly, tau phosphorylation at Ser422 followed by truncation at Asp421 were found to be precursors to neuronal tau inclusions such as NFTs and Pick bodies, but not the glial inclusions found in PSP and CBD (Guillozet-Bongaarts et al., 2007).
Argyrophilic grain disease (AGD) is a late-onset dementia, sometimes classified as a form of FTD-tau. PSP is the most frequent clinical diagnosis for patients with AGD pathology, yet clinical manifestations also include amnestic cognitive impairment that is typically milder than that of AD, or less commonly behavioral disturbances (Gil et al., 2018; Steuerwald et al., 2007). AGD has been linked to higher frequency of the MAPT H1/H1 haplotype (Gil et al., 2018). Like PSP and CBD, AGD is a 4R-tauopathy. It is characterized by small, argyrophilic, dot or comma-shaped inclusions in neuronal dendrites known as argyrophilic grains; this pathology is found mainly in the entorhinal cortex and hippocampus. Other pathologies include pretangles (Figure 2A) in limbic projection neurons and oligodendroglial coiled bodies (Figure 2F) in the hippocampal and peri-amygdaloid white matter (Ferrer et al., 2008). Accumulation of tau pathology in AGD is proposed to start in the ambient gyrus, extending to the anterior and posterior medial temporal lobe, and finally the septum, insular cortex and anterior cingulate gyrus (Saito et al., 2004). Although severe atrophy of the affected regions is typically observed, cognitive impairment tends to be milder than other types of dementia. Ballooned neurons in the amygdala are evident (Tolnay and Probst, 1998).
5.2 AD is a secondary tauopathy
AD is the leading cause of dementia in patients over 65 years of age. Most AD cases are sporadic; only 5% are genetic. Mutations in APP, PSEN1, and PSEN2 are known to cause autosomal dominant AD; all of them increase amyloid burden by affecting processing of the amyloid precursor protein. In addition, over 70 genes or loci have been proposed to contribute to AD risk (Reitz et al., 2023), such as the APOE-ε4 allele. Although tauopathies are a predominant feature of AD, a causative link between MAPT mutations and AD has not been identified. Moreover, the underlying mechanism linking Aβ and tau remains elusive.
In AD, 3R-tau+ and 4R-tau+ intraneuronal inclusions follow the accumulation of extracellular Aβ plaques. These include classic flame-shaped NFTs (Figure 2A), neuropil threads (NTs), and plaque-associated tau+ dystrophic neurites (Figures 2B,C). Tau pathologies first appear in the entorhinal cortex, then spread topographically to the hippocampus, limbic structures, and finally the neocortex (Braak and Braak, 1991). In AD, tau undergoes sequential phosphorylation and conformational changes that are thought to trigger the formation of paired helical filaments (PHFs), the main tau conformation within NFTs (Binder et al., 2005; García-Sierra et al., 2003; Mondragón-Rodríguez et al., 2008). P-tau epitopes, such as T181 and T231, may represent early stages of pathology, whereas pS202/T205 and pS396/404 represent late stage of pathology (Augustinack et al., 2002). Two hexapeptide motifs in the MTBR, VQIINK and VQIVYK, form the core of AD PHFs; these motifs are shielded from the extracellular environment in native tau but are exposed in tau monomers isolated from AD brains (Chen et al., 2019).
AD diagnosis is confirmed postmortem by the presence of both Aβ plaques and AT8+ or silver+ NFTs. As mentioned above, Aβ plaque severity is rated according to Thal staging (Thal et al., 2002), while the severity of neurofibrillary changes (NFTs, NTs, and pretangles) are rated according to Braak staging (Braak and Braak, 1991). Although many tau antibodies (Table 2), recognize disease-associated tau phosphoresidues and/or aberrant tau conformations, AT8-immunoreactivity (-ir) is used as the standard for Braak staging (Del Tredici and Braak, 2020). In this system, stages I-II correspond to NFT accumulation in the transentorhinal regions, II-III adds presence of NFTs in the limbic regions, and V-VI are considered end-stages of AD with widespread NFTs in the isocortical association areas.
6 Aged NHPs can present sporadic tau pathologies in the CNS
To delve into the question of whether NHPs present age-related tau pathologies we search in PubMed up to December 2024. Keywords included “nonhuman primate,” “monkey,” “marmoset,” “macaques,” “prosimian,” “ape,” “tau,” “neurofibrillary tangles,” “tauopathies,” “phosphorylated tau,” “age,” “old” combined with peer-reviewed and English language as filters. Reference lists in original research and review articles were examined to gather additional publications. Title and abstracts were screened for topic relevance. Fifty-two articles describing original peer-reviewed studies in NHPs were selected and analyzed to extract information on findings per species; see Tables 3–6 for compiled references and corresponding data. To understand the frequency of tau pathologies in NHPs, we considered the number of studies and subjects, as well as the number of positive cases detected and their age; see Figure 3 for a comparison of ages across human and example NHP species based on biological milestones.
Table 3. Peer-reviewed publications on tau immunoreactivities in aged great apes.
Table 4. Peer-reviewed publications on tau immunoreactivities in aged Old World monkeys.
Table 5. Peer-reviewed publications on tau immunoreactivities in aged New World monkeys.
Table 6. Peer-reviewed publications on tau immunoreactivities in aged prosimians.
Figure 3. Approximate age in years (yrs.) of life milestones across female species from representative primate families. Chimpanzees reach sexual maturity between 8.5–14 yrs. of age and are on average 15 yrs. old when they first give birth (Walker et al., 2018); their fertility declines in their 30s and experience menopause at 45–50 yrs. old (Wood et al., 2023). In rhesus, first birth often occurs at age 4 (Pittet et al., 2017) and their fertility declines around age 17 (Lee et al., 2021); menopause was reported by 24–26 yrs. old (Walker, 1995). Common marmosets are considered primed adults between 2 and 8 yrs. of age, although they do not seem to undergo reproductive senescence (Abbott et al., 2003). Gray mouse lemurs reach sexual maturity around 0.5 yrs. (Hohenbrink et al., 2015) and, like common marmosets, do not seem to experience reproductive senescence. Their median lifespan is 5.5 yrs. (Martine and Aude, 2022) but can live up to 18 yrs. in captivity. Listed maximum lifespans in NHPs are estimated for captive animals. Mature tau pathologies, like NFTs, have been reported in extremely old animals nearing their respective species’ maximum lifespan, yet without behavioral or clinical correlates, it is difficult to assert whether tau pathology affects survivability. Created in https://BioRender.com.
Our systematic analyses of the literature identified a few reports of sporadic tau inclusions in the brain of aged NHPs. Our criteria for detection of NFTs (or other disease-associated tauopathies) in a publication was the authors’ description of the intraneuronal inclusion positive for silver and/or AT8 staining, with a corresponding image. We differentiated between AT8+ inclusions from AT8-ir and included descriptions of tau immunoreactivities detected by other tau antibodies. Most studies of age-related tau pathologies were performed in Old World monkeys. Captive animals were examined, except for one study in wild mountain gorillas; behavioral evaluations were seldom performed. Compared to human studies, which utilized silver and/or AT8 staining for confirmation of tau pathology, especially for NFTs, NHP studies have utilized a variety of tau antibodies.
6.1 Aged great apes
Eleven studies have examined great apes for evidence of tau pathologies encompassing 34 chimpanzees, 20 gorillas, and 5 orangutans; most of the animals were >30 years old (Table 3). Overall, NFTs were reported in six chimps aged ≥39 years (Edler et al., 2017; Rosen et al., 2008). Rosen et al. (2008) identified a 41-year-old chimp that had NFTs highly similar to those found in human disease. Edler et al. (2017) reported NFTs in five chimps of which three were classified with Braak staging 1/II and one with stage V; the fifth chimp had NFTs exclusively in the prefrontal cortex. NFTs have not been identified in gorillas and orangutans.
With regards to AT8-ir, chimps aged ≥37 years presented AT8+ pretangles, neurite clusters, and NTs mainly in the neocortex (Edler et al., 2017; Rosen et al., 2008). In gorillas, AT8+ pretangles were not observed, although AT8+ glia and neurite clusters were found in the frontal cortex of eight ≥35-year-old wild mountain gorillas and a 55-year-old Western lowland gorilla (Perez et al., 2013; Perez et al., 2016). The latter 55-year-old gorilla also had AT8+ glia and neurite clusters in the hippocampus.
Other tau antibodies have been utilized to identify tau accumulations in great ape brains. Notably, a 41-year-old chimp had PHF1-ir and MC1-ir in neuritic plaques and threads, but to a lesser extent than AT8-ir (Rosen et al., 2008). Aged Western lowland gorillas (≥49 years) had occasional Alz50-ir and MC1-ir neurite clusters in the neocortex (Perez et al., 2013). Wild mountain gorillas aged ≥16 years had rare Alz50-ir NCs in the frontal cortex (Perez et al., 2016).
6.2 Aged Old World monkeys
In comparison to great apes, 32 reports in Old World monkeys studied the presence of tau pathologies in 141 rhesus macaques, 100 cynomolgus macaques, 2 Japanese macaques, 62 baboons, 67 African green monkeys, and 2 Campbell’s guenon, with ages ranging 1–41 years (Table 4). NFTs were reported by Paspalas et al. (2018) in the entorhinal cortex of one 38-year-old rhesus monkey, while Kiatipattanasakul et al. (2000), Oikawa et al. (2010), and Uchihara et al. (2016) found them in the thalamus, entorhinal cortex, or hippocampus of four cynomolgus macaques aged ≥32 years. Schultz et al. (Schultz, Dehghani, et al., 2000) described NFTs in the hippocampus of two ≥26-year-old baboons and Cramer et al. (2018) in the entorhinal cortex and hippocampus of two African green monkeys aged ≥20 years. NFTs were not detected in aged Japanese macaques and Campbell’s guenons (Härtig et al., 2000; Kuroki et al., 1997).
AT8-ir has been detected in the brain of aged Old World monkeys. Six studies reported results of AT8 immunostaining in rhesus. In these animals, neuronal AT8-ir was found in the entorhinal cortex and hippocampus starting around ≥24 years of age, although one 16-year-old monkey harbored pretangles restricted to the amygdala (Barnes et al., 2024). Four ≥28-year-old rhesus from three separate studies had amygdala and/or prefrontal cortex AT8-ir (Barnes et al., 2024; Datta et al., 2021; Paspalas et al., 2018), but no rhesus has yet been reported to harbor Braak stage V/VI tauopathy. Of these reports, Paspalas et al. (2018) identified AT8+ fibrils with an ultrastructure resembling human AD PHFs. Five reports have examined AT8-ir in cynomolgus macaques. Like rhesus, the hippocampus and temporal cortex were common sites of neuronal AT8-ir in cynomolgus aged ≥26 years (Oikawa et al., 2010; Uchihara et al., 2016). Additionally, one report described AT8-ir in the basal ganglia and neocortex of ≥30-year-olds. These same animals harbored AT8+ pretangles and oligodendrocyte-like cells that only colocalized with 4R-tau (Uchihara et al., 2016). Interestingly, diffuse AT8-ir was observed in neuronal soma of the hippocampus and prefrontal cortex of 14- to 19-year-olds cynomolgus (Jester et al., 2022). Among four reports, baboons aged ≥19 years were found to have neocortical AT8-ir in neurons and glia, preferentially in the medial temporal lobe, with substantial interindividual variation (Härtig et al., 2000; Ndung'u et al., 2012; Schultz et al., 2000a; Schultz et al., 2000b). Two of three reports in African green monkeys identified AT8-ir in animals aged >20 years (Cramer et al., 2018; Lemere et al., 2004). In two animals, AT8-ir occurred as pretangles in the entorhinal cortex and hippocampus (Cramer et al., 2018), and a third animal had sparse AT8-ir in neuritic plaques of the temporal cortex (Lemere et al., 2004). Atypically, one study found granular cytoplasmic AT8-ir in small cells throughout the neocortex, mainly the superior occipital gyrus, in the striatum, and rarely in the hippocampus of African green monkeys aged ≥8.2 years (Latimer et al., 2019). Lastly, one report of two guenons aged 27 and 30 years detected rare AT8-ir cells in the cingulate cortex (Härtig et al., 2000).
Other notable findings in Old World monkeys include PHF1-ir in neuritic amyloid plaques in rhesus aged ≥25 years (Shah et al., 2010), and the presence of AT8+, PHF1+, and TG3 + perivascular astroglial inclusions and oligodendroglial coiled bodies in the limbic system of a 30-year-old baboon. Approximately 10% of the tau inclusions in the baboon were argyrophilic (Schultz et al., 2000a). In a 35-year-old cynomolgus macaque, argyrophilic glial fibrillary tangles were found in the striatum, thalamus, midbrain, and brainstem (Kiatipattanasakul et al., 2000).
6.3 Aged New World monkeys
Ten studies have examined tau pathologies in New World monkeys, encompassing 65 common marmosets, 36 cotton top tamarins, and 38 squirrel monkeys between 1 and 24 years old (Table 5). Common marmosets presented AT100-ir and Alz50-ir in dystrophic microglia of 1- to 18-year-old common marmosets that increased with age (Rodriguez-Callejas et al., 2016). AT8-ir was reported as negative in one study of marmosets aged 7–10 years (Freire-Cobo et al., 2023). Silver staining has not been evaluated in marmosets. Cotton top tamarins and squirrel monkeys were negative for argyrophilic NFTs. Squirrel monkeys (number of subjects not disclosed) had occasional AT8+ and Alz50+ cortical neurons and neuritic plaques (Elfenbein et al., 2007).
6.4 Aged prosimians
In prosimians, six studies evaluated the brains of 163 gray mouse lemurs aged 1–13 years, and one report evaluated 2 Brown lemurs aged 12 and 14 years (Table 6). Of these studies, only one examined argyrophilic NFT occurrence in 25 gray mouse lemurs and reported negative results (Bons et al., 1992). AT8-ir has not been explored in gray mouse lemurs and was only reported in one 12-year-old Brown lemur (Härtig et al., 2000). Other reported tau-related findings include weak neocortical PHF tau in few gray mouse lemurs aged 7–13 years (Bons et al., 1995a; Bons et al., 1995b), and faint CP13-ir in a few scattered hippocampal cells of three gray mouse lemurs aged 6–11 years (Kraska et al., 2011).
6.5 Age- or disease-related tau pathologies in NHPs?
An analyses of the above listed reports supports the concept that aged chimps (Edler et al., 2017; Rosen et al., 2008; Rosen et al., 2011), rhesus (Paspalas et al., 2018), cynomolgus (Kiatipattanasakul et al., 2000; Oikawa et al., 2010; Uchihara et al., 2016), baboons (Schultz et al., 2000a; Schultz et al., 2000b), and African green monkeys (Cramer et al., 2018) can develop tau pathologies, identified as classic argyrophilic or AT8+ NFTs. Evidence of NFTs is still missing in aged gorillas, orangutans, Campbell’s guenon, common marmoset monkeys, squirrel monkeys, cotton top tamarins and lemurs (Tables 3–6). The number of subjects with tau inclusions is overall small but the overall number of aged subjects is also small.
A critical issue to consider is how an “aged animal” is defined, which depends on the NHP species. The interpretation of the results is affected by the chosen method to match ages between NHPs and humans, and whether the age matching considers lifespan and reproductive senescence (Figure 2). This issue is especially important for New World monkeys and prosimians, as it is currently unknown at what age females experience a decline in fertility and may have affected the detection of tau pathologies.
The clinical diagnosis of AD or FTD is complex and requires multimodal evaluations over time, including records of cognitive or executive and/or motor impairment, fluid biomarkers, and/or imaging. Misdiagnoses, especially between FTD and primary psychiatric disorders, are not uncommon (Ducharme et al., 2020). Diagnoses are ultimately confirmed postmortem by the presence of specific proteinopathies characterized by their neuroanatomical distribution, burden, and morphology. The sole postmortem identification of a few tau pathologies (or AT8-ir neurons) is not considered a diagnosis of tauopathy. Interestingly, most reports in old NHPs did not aim to identify tauopathies but rather to assess whether AD-like pathology was present as an indication of the animals developing or having AD.
Age-related neurological changes in NHPs such as cognitive and motor dysfunction (Emborg et al., 1998; Hopkins et al., 2021; Moore et al., 2006), brain atrophy on MRI (Kraska et al., 2011; Sridharan et al., 2012), variations in CSF and blood biomarkers (Darusman et al., 2014; Latimer et al., 2019; Metzler et al., 2025; Yue et al., 2014) and postmortem tau inclusions (listed above), have been documented. Yet, most studies have seldom evaluated multiple domains per animal in statistically powered projects due to the low availability of aged NHPs, high cost of multiple evaluations, and academic pressures to produce results. Opportunistic sampling of postmortem tissue has emerged as an efficient way to probe specific questions, albeit with the limitation of forfeiting a valid diagnosis of AD, FTD, or other neurodegenerative disease. For example, the identification of NFTs in >37-year-old chimps (Edler et al., 2017) demonstrate the vulnerability of the species to harbor tau pathology, although a tauopathy diagnoses cannot be asserted due to missing behavioral data.
Tauopathies may occur in NHPs. The 38-year-old macaque harboring NFTs identified by Paspalas et al. (2018) had “pronounced cognitive deficits” defined by the greater number of trials the animals needed to learn a delayed non-match-to-sample task compared to younger macaques. A caveat is that age-related decline is expected in NHPs, and this was the only advanced age animal tested in the study. Barnes et al. (2024) aimed to ascertain AD diagnoses in aged rhesus by applying the ABC and ATN diagnostic scales; the investigators combined postmortem results with in vivo cognitive and MRI data. Although the NHPs presented AT8-ir, none of the aged subjects had NFTs. The cynomolgus with PSP-like pathologies in the report by Kiatipattanasakul et al. (2000) had gait disturbance and involuntary trembling supporting a potential PSP disease condition that may differ from age-related decline. These findings suggest that NHPs could develop tauopathies; application of current standards of disease diagnoses is needed for confirmation. Overall, the question of whether NHPs can develop AD or FTD waits to be fully answered.
7 NHP models of tauopathy
Although some aged NHPs, like some aged humans, can develop disease-like pathology, the accumulated data show that investigators cannot rely on identifying enough affected monkeys to conduct studies powered for systematic evaluation of disease mechanisms or novel therapies. The alternative is to create NHP models of tauopathy by treating animals with different agents that may induce a disease-like condition.
To investigate currently available NHP models of tauopathies we expanded our PubMed search on aged NHP pathologies to include the keywords “models,” “Alzheimer’s disease” and “frontotemporal dementia.” We also examined reference lists in review articles to gather additional articles and focused on peer-reviewed articles in English. Fifteen articles that reported on the expression of tau were selected and analyzed to extract information on findings per species. See Tables 7–9 for compiled references and corresponding data on NHP models of tauopathy, with exception of three reports on transgenic models (discussed in section 7.4).
Table 7. Peer-reviewed publications intracerebral delivery of brain homogenates to NHPs.
Table 8. Peer-reviewed publications reporting intracerebral delivery of synthetic Aβ peptides and oligomers (as described by authors) to NHPs.
Table 9. Peer-reviewed publications reporting intracerebral delivery of viral vector to NHPs.
Most publications focused on tauopathies secondary to Aβ pathology. Only three peer-reviewed reports (Beckman et al., 2021; Beckman et al., 2024; Darricau et al., 2022) utilized methods to produce primary tauopathies in NHPs. Methods for generating NHP models included intracerebral delivery of brain homogenates or protein extracts from patients, synthetic Aβ oligomers (AβOs), or viral vectors to increase Aβ or tau burden in adult animals. A similar concept of modeling by increasing Aβ burden has been applied by combining viral vectors and reproductive technologies to generate transgenic NHPs carrying disease-related mutations. All studies performed postmortem pathological evaluation; antemortem behavioral studies were rarely conducted. As described in the section for aged NHPs, our criteria for NFT detection in a publication on NHP models of tauopathy was the authors’ description of the intraneuronal inclusion positive for silver and/or AT8 staining, with a corresponding image.
7.1 Models based on intracerebral delivery of brain homogenates or protein extracts
Starting in the early 1990s, five studies explored whether tauopathies developed after intracerebral delivery of brain homogenates from patients with a range of conditions to common marmosets, lemurs, and rhesus (Baker et al., 1993; Darricau et al., 2024; Darricau et al., 2022; Gary et al., 2019; Ridley et al., 2006) (Table 7).
Baker et al. (1993) produced the first publication aiming to induce AD pathologies in marmosets. The investigators injected three 2–3 years old marmosets in the left caudate and hippocampus, the right nucleus accumbens and amygdala, and both parietal cortices with brain homogenates from a single patient with early onset AD. At necropsy, approximately 6.5 years later, the marmosets presented Aβ plaque-like pathologies and occasional angiopathy in the cerebral cortex and amygdala, but not in deeper brain structures. NFTs were not detected; the antibody utilized for tau identification was not specified.
A follow-up study by Ridley et al. (2006) described injecting marmosets (<10 years old or >10 years old) in the same intracerebral sites as the Baker study with various brain homogenates. Nine marmosets were injected with samples obtained from three sporadic AD cases, five marmosets were injected with homogenate from one familial AD case attributed to a codon 717 mutation in APP, six marmosets were injected with samples obtained from two cases of cerebral amyloid angiopathy (CAA) associated with Down syndrome, and two marmosets were injected with homogenate from one case of spongiform encephalopathy associated to a prion protein gene mutation; this brain also contained cerebral β-amyloidosis (Ridley et al., 2006). The investigators also injected five animals with brain homogenates from three marmosets previously injected with an AD brain homogenate; these subjects were part of the above-mentioned Baker et al. (1993) study. Of the 27 injected marmosets, 24 displayed differing degrees of Aβ plaques and CAA in the brain at >6 years post-injection. The three monkeys without Aβ pathology had received brain homogenates from a sporadic AD case, a familial AD case, and a previously injected marmoset, respectively. None displayed NFTs or tau-ir; as in the previous publication, the antibody utilized for tau detection was not specified.
More recently, Gary et al. (2019) reported the effects of injecting six young (3.5-year-old) grey mouse lemurs in four sites surrounding the parietal cortex with brain homogenates from AD patients; an additional six lemurs of the same age were injected with brain homogenates from healthy patients. One year and a half later, the AD brain-inoculated lemurs displayed progressive cognitive impairment but no motor dysfunction, abnormal electroencephalograph signals, and cerebral atrophy on MRI. Postmortem, Aβ plaques or CAA were detected in all five AD-inoculated animals; phosphorylated tau evaluated by AT8, MC1, and AT100 immunostaining, was only detected in two of these animals, NFTs were not found. Interestingly, the authors noted that the two animals with phosphorylated tau immunoreactivities displayed the greatest hippocampal neuronal loss and worst memory scores. Also of interest, the animal that developed CAA was inoculated with the only AD brain homogenate that displayed CAA, suggesting that different protein strains may induce differing pathology.
Using a different brain homogenate treatment, Darricau et al. (2022, 2024) produced two consecutive reports on rhesus macaques. In the first study (Darricau et al., 2024; Darricau et al., 2022), two ~7 years old rhesus monkeys were injected into the supranigral area with sarkosyl-insoluble tau seeds extracted from the frontal cortex and mesencephalon of two PSP patients, one with pure PSP pathology, and one with a combination of PSP and Braak stage II AD tauopathy. Two additional rhesus macaques received homogenates from the frontal cortex of two control brains, one of which was devoid of pathology and the other with Braak stage II tauopathy and Thal stage 1 amyloid deposition. It should be noted that each monkey was injected solely with one single donor brain extract (PSP or control). At 6 months post-injection, the two macaques that received PSP seeds displayed parkinsonian-like motor impairments including increased step duration, decreased step length, and decreased range of motion. They also performed worse than the control macaques on “harder” trials of an object retrieval task. The animals were euthanized at 1.5-years post-injection and AT8-ir was observed in the supranigral area, ventral thalamus, substantia nigra, and globus pallidus of the PSP-injected macaques. Importantly, tau pathologies presented as NFTs, neuropil threads, tufted astrocytes, and coiled bodies; only 4R tauopathies were observed. In the second publication (Darricau et al., 2024; Darricau et al., 2022), macaques received purified tau extracted from brains of AD patients (AD-tau) with or without synthetic amyloid-β oligomers (AβOs). AD-tau injections induced AT8+ neuropil threads in the hippocampus, entorhinal cortex, and cingulate cortex at 1.5 years post injection. NFTs were only observed in macaques that received AD-tau plus AβOs.
The studies utilizing intracerebral injection of brain homogenates from patients demonstrate the feasibility of testing the pathogenic potential of a specific sample and its capacity to spread the affected proteins in a prion-like manner to interconnected brain regions. Issues associated to neurosurgical technique, e.g., brain targeting accuracy and backflow of infusate through the needle track, may affect protein distribution and accumulation and needs to be considered for interpretation of the results. For modeling purposes, the variability across donor tissues and sample preparation can influence the replicability of the syndrome; biochemical characterization of donor tissue prior to injection may help overcome this issue. Of the 5 studies utilizing human brain homogenates for disease modeling in NHPs (Table 7), only the two reports by Darricau et al. removed potentially seed-competent contaminants from their donor sources by performing sarkosyl-insoluble tau extractions from PSP and AD patients, respectively (Darricau et al., 2024; Darricau et al., 2022).
7.2 Models based on CNS delivery of aβ peptides and synthetic AβOs
In addition of the above-mentioned report by Darricau et al. (2024) that combined AD-tau with AβOs, five studies tested the effects of Aβ peptides or AβOs (as reported by the authors) in marmosets, rhesus macaques, cynomolgus macaques, and African green monkeys (Forny-Germano et al., 2014; Geula et al., 1998; Ridley et al., 2006; Wakeman et al., 2022; Yue et al., 2021) (Table 8).
In the first of these reports by Geula et al. (1998), the investigators intracerebrally injected fibrillar Aβ to one 5- and two 25-28-year-old rhesus macaques. After 11–12 days, diffuse Aβ accumulation sometimes accompanied by a core structure was present at the injection site of the older macaques, as well as an area of neuron loss extending up to 1.5 mm from the injection site. pSer262-tau-ir neurons and neurites were also present up to 2 mm from the injection site. Comparatively, the 5-year-old macaque had limited p-tau-ir. Injections of soluble Aβ40 and PBS vehicle also did not produce a robust response. The investigators also injected fibrillar Aβ to young (2-3 yrs) and aged (8-10 yrs) common marmosets. The aged marmosets had Aβ accumulation and p-tau-ir, although less than the aged macaques. Silver staining and AT8-ir were not evaluated.
The above-mentioned report by Ridley et al. (2006) included a group of six marmosets that were injected with AβOs in the left caudate and hippocampus, the right nucleus accumbens and amygdala, and both parietal cortices. No NFTs or Aβ plaques were found in the monkeys for up to 10 years post-injection.
Later, Forny-Germano et al. (2014) delivered AβOs to the lateral ventricles of 9- and 16-year-old cynomolgus macaques. Injections were given once every 3 days for up to 24 days. Seven days after the final injection, AβOs were detected in neurons of the cortex, hippocampus, striatum, and amygdala. The authors also reported an increase in pSer396-tau, AT100, and CP13 immunopositivity in these regions, as well as increased AT8, Alz50, and PHF-1 immunopositivity in the frontal cortex. Interestingly, thioflavin-S-positive NFTs were observed in the neocortex. Immunogold electron microscopy with antibodies MC-1, Alz50, and PHF-1 confirmed the presence of tau filaments in the frontal cortex. NFTs were not detected.
Yue et al. (2021) also treated cynomolgus macaques with AβOs. Seven 20–22-year-old monkeys received bilateral AβO injections above the hippocampus between the lateral basal ganglia and medial temporal lobe at four different time points over 150 days. At >240 days after the last injection, all seven monkeys developed Aβ plaques in a similar spatial distribution, though plaque density varied greatly between subjects. Notably, two of the AβO-injected macaques had a similar number of plaques in the brain as non-injected control subjects. All but one AβO-injected monkey developed NFTs and NTs in several brain regions that were labeled by silver, AT8, and AT100.
Lastly, Wakeman et al. (2022) injected 9-10-year-old male African green monkeys with AβOs either via the intrathecal (n = 23) or intracerebroventricular (n = 2) route. Intrathecal dosing was given either one or three times per seven-day period for 28 days total, and the animals were euthanized either 7, 28 or 48 days after the last injection. Intracerebroventricular dosing was done three times per seven-day period for 28 days, and the animals were euthanized 7 days after the last injection. The investigators reported increased AT8-ir in the medial temporal lobe for both delivery methods, but the only statistically significant finding was increased AT8+ cells in the outer layers of the entorhinal cortex following intrathecal injections. Overt Aβ plaques or NFTs were not observed.
NHP models based on the injections of synthetic protein seeds present an opportunity to study prion-like spread of pathologies between interconnected brain regions. Similar to injections of brain homogenate neurosurgery-related issues need to be considered for interpretation of protein distribution. As investigators control the characteristics of the injected material, this method has the potential to generate replicable results and can be advantageous for modeling and assessing pathogenicity of different protein strains. The five available reports on this model injected various Aβ strains to NHPs with variable tau-related outcomes. NFTs were only detected in cynomolgus macaques that received 800 μg AβOs and were evaluated 240 days to 1 year later (Yue et al., 2021), but not with shorter period of times, e.g.: 7 days (Forny-Germano et al., 2014) or 84 days (Wakeman et al., 2022). These results suggest that an extended period of time may be required for NFT generation after AβOs. Thus far, no group has reported injection of tau seeds into NHPs.
7.3 Models based on intracerebral delivery of viral vectors
Three reports utilized intracerebral delivery of viral vectors to overexpress mutated or wild type tau protein in rhesus macaques (Beckman et al., 2021; Beckman et al., 2024; Jiang et al., 2024) (Table 9).
Beckman et al. (2021) injected four rhesus aged 10–15 years in the left entorhinal cortex with an adeno-associated virus serotype 1 vector encoding for 0N4R tau with the P301L/S320F mutations (AAV1-P301L/S320F). The same animals also received an AAV-green fluorescent protein (AAV1-GFP) injection in the contralateral entorhinal cortex; eight additional non-injected animals were used as young and aged controls. The authors proposed this approach for modeling AD, although tau mutations P301L and S320F are each independently linked to genetic FTD (Strang et al., 2019). Ninety days post-AAV delivery, the animals were euthanized. CSF and plasma collected antemortem showed significant increases in neurofilament light chain (NfL), total tau, sTREM2, TNFα, IL-6, pS199-tau, and pS396-tau. In the entorhinal cortex and hippocampus ipsilateral to AAV1-P301L/S320F delivery, many neurons were AT8+. Furthermore, NFTs (ThioS+/NeuN+) and ghost tangles (ThioS+/NeuN-) were detected in the hippocampus. In the contralateral, AAV-GFP-treated hippocampus, fibrillary tau pathology was not detected, although pSer262-tau-ir and pThr231-tau-ir were observed. Immunofluorescence revealed colocalization of 3R-tau-ir and 4R-tau-ir with AT8-ir in both hippocampi and entorhinal cortices. The authors proposed that the colocalization of AT8-ir and 3R-tau-ir was indicative of permissive templating of endogenous 3R-tau by the mutated exogenous 4R-tau and prion-like spread to interconnected brain regions. AT8-ir was also detected in the occipital lobe, retrosplenial cortex, and visual regions V4 and V1, suggesting protein spread from the injection site to interconnected brain regions. It should be noted that images from control brains were not provided.
A follow up study by Beckman et al. (2024) injected eight rhesus aged 10–16 years in the left entorhinal cortex with the same double-mutant 0N4R tau construct (AAV1-P301L/S320F). Four additional monkeys received an empty vector control (AAV1-CTR) in the left entorhinal cortex. Half of the animals were followed for 90 days, and the other half for 180 days. Antemortem CSF biomarkers were elevated in the AAV1-P301L/S320F group beginning at different time points post-injection; pS199-tau at 30 days, total tau and pS396-tau at 60 days, pT231-tau at 90 days, and pT181-tau at 120 days. NfL was increased in CSF at 30 days and serum at 60 days, while Brain Derived Neurotrophic Factor was decreased in CSF at 60 days and in serum at 90 days. In AAV1-P301L/S320F animals, antemortem imaging at 90 and 180 days detected a decreased in left hippocampal volume by MRI and a significant increase in uptake of tau radiotracer [18F]APN-1607 by PET. Postmortem, these monkeys had AT8+ pretangles in the left hippocampus and entorhinal cortex, as well as in the right entorhinal cortex that were more frequent in the 180 days group. They also had mature NFTs (AT8+/ThioS+/NeuN+) and ghost tangles (AT8-/ThioS+/NeuN-) in these regions that were also more frequent in the 180 days group. Similar to the investigators’ previous report, colocalization of AT8-ir and 3R-tau-ir was observed in the left entorhinal cortex and hippocampus, especially in the 180 days group. Several other tau immunoreactivities, including TOC1, Alz50, pS422-tau, TNT2, Tau5, TauC3, PHF1, MN423 were also detected.
Lastly, Jiang et al. (2024) overexpressed human 4R-tau in the hippocampi of 11 adult rhesus macaques (aged 7–16 years) using FLP/FRT-mediated recombination. The animals were injected with an AAV9 vector expressing a flippase recognition site (FRT) and 4R-tau under control of a CAG promotor (rAAV9 CAG::FRT-hTau), as well as an AAV9 vector expressing the recombinase flippase (FLPo) under a human synapsin promoter (rAAV9 Syn::FLPo). Seven additional animals received control injections of AAV9 CAG::FRT-hTau, which cannot express human tau without FLPo/FRT-mediated recombination. A subset of the tau-expressing (n = 7) and controls (n = 2) animals also received AAV9 Syn::GFP in the hippocampus. At 42 days post-injection, the tau-expressing animals displayed hippocampal atrophy on MRI, decreased metabolic activity by [18F]Fluoro-deoxy-glucose-PET, and increased uptake of the tau radiotracer [18F]T807 on PET. At 56 days, these monkeys showed impairments on spatial working memory and delayed match-to-sample tests compared to their preoperative baseline performance and control animals. Additionally, at 84 days they had increased CSF levels of total tau, pT181-tau, pT231-tau, NfL, and decreased Aβ42 compared to controls. The monkeys were euthanized at either 42-70-days or 350-days post-injection; the number of animals per time point is unclear. AT8-ir and pT231-tau-ir were detected in hippocampal neurites and soma in a 42-day tau-overexpressing monkey. Further histological analyses identified increased 3R- and 4R-tau-ir and neuron loss (indicated by reduced NeuN-ir and Nissl) in the hippocampus of tau-overexpressing subjects compared to controls.
Models generated by viral vector gene transfer increase protein burden by overexpression of the encoded protein. Reliable viral vector production and quality control of the produced titer is critical for replicability of the approach. Studies on protein transmission relying on these types of models should consider differences in anterograde or retrograde transport capabilities of viral vectors subtypes that could contribute to protein spreading and therefore confound the results, in addition to intracerebral targeting accuracy and/or backflow of infusate through the needle track. Viral vector gene transfer methods are particularly advantageous for studying disease-related mutations and their associated changes in the transcriptome and interactome. Careful selection of the gene (or part of the gene) to be overexpressed is critical for model development. Beckman et al. (2021, 2024) created an NHP model expressing double tau mutations P301L and S320F and Jiang et al. (2024) overexpressed non-mutated human 4R-tau. NFTs were only identified by Beckman and colleagues mainly at 180 days, underscoring the importance of time for the development of tau aggregates.
7.4 Transgenic models
Three reports utilized gene transfer of mutant human amyloid precursor protein (APP) gene to gametes or embryos to create transgenic models of AD in cynomolgus, rhesus, and common marmoset monkeys (Chan et al., 2022; Seita et al., 2020; Yoshimatsu et al., 2022).
Seita et al. (2020) transfected oocytes of cynomolgus monkeys with lentiviral vectors encoding for APP with either the Swedish mutation K595N/M596L, the Arctic mutation E618G, or the Iberian mutation I641F. Two female transgenic macaques were birthed; their plasma levels of Aβ40 and Aβ42 were 2- and 50-fold higher, respectively, compared to a wild type monkey. Two transgenic fetuses were aborted at embryonic days 101 and 102; the aborted fetuses had increased insoluble Aβ42 compared to an aborted wild type fetus. Neither Aβ-ir nor p-tau AT8-ir accumulation was detected in the fetal brain tissue.
Chan et al. (2022) also utilized lentiviral vectors to generate AD-like transgenic monkeys. The investigators transfected rhesus macaque oocytes with a lentiviral vector encoding for human APP carrying Swedish mutation K670M/N671L and Indiana mutation V717F. Two female transgenic rhesus were birthed and followed for 10 years. No volumetric brain differences were detected by MRI between APP mutation carriers and wild type controls. CSF levels of Aβ42, total tau, and pT181-tau were measured at 2, 4, 6, 8, and 9 years of age. Transgenic monkeys had elevated Aβ42 at 4 years of age and increased total tau at 2 and 4 years of age, but no difference in pT181-tau levels. Behaviorally, the transgenic animals presented some anxious behaviors and executive function deficiencies. At necropsy, only one of the transgenic monkeys displayed Aβ plaque deposition and CAA in the neocortex. CP13-ir was not detected.
Yoshimatsu et al. (2022) generated two transgenic marmosets harboring human APP with Swedish mutation K670M/N671L and Indiana mutation V717F via lentiviral transduction to pronuclear stage embryos. Genomic analysis showed that these transgenic marmosets were identical twins, yet one of the marmosets harbored ~3-fold more transgenic cells than the other. Postmortem analysis was performed at 7 years of age. One of the two marmosets had small Aβ plaque-like structures in the prefrontal cortex. Neither marmoset had AT8-ir.
Transgenic animals overexpressing pathogenic mutations present an opportunity for comprehensive disease modeling and for assessing pathogenesis across the lifespan of the monkeys; cohorts of animals could be generated by reproduction of mutated carriers. This approach presents many challenges associated to the availability of animals devoted to in vitro fertilization, and the complexity of the methods (for review see Schmidt et al., 2022). Furthermore, the development of the disease may require years, hampering research progress. Seita et al. (2020), Chan et al. (2022), and Yoshimatsu et al. (2022) generated transgenic macaques carrying multiple APP mutation; tauopathies were not identified probably because the monkeys were young at the time of necropsy. The generation of models with multiple mutations may speed up the development of pathology, yet it is not the most clinically relevant as multiple mutations are rare in human populations. Thus far, no groups have reported germline or embryonic modification of MAPT in NHPs.
8 Final thoughts
As stated in the introduction, the main aim of this article was to analyze available reports on tau pathologies and models of tauopathies in NHPs, considering the complexity of the tau protein and associated tau pathologies. Our exploration identified gaps in knowledge, as well as differences in the methods of evaluation and the criteria applied to identify pathologies and define a pathological condition across human and NHP species. In this final section, we discuss how to maximize current NHP tauopathy models, emerging paradigms for generating new models, and the ethical challenges associated with the study of tauopathies in NHPs.
8.1 Increasing the translational value and validity of current NHP models of tauopathy
NHP models of tauopathies are urgently needed for studying disease mechanisms and test first-in-class and invasive therapies. Recognizing the advantages and limitations of the different models is the first step toward identifying the best match to answer a scientific question.
Old NHPs are ideal models for the study of aging and tau pathologies (section 6) and may be more susceptible to experimentally induced tauopathies. Some animals may develop disease-like tau pathology; few reports have also documented behavioral changes that combined with the pathology may indicate primary or secondary tauopathy (Kiatipattanasakul et al., 2000), a possibility that requires systematic investigation. Addressing the gaps in knowledge regarding both human (section 2) and NHP (section 3) tau in physiological conditions would further shed light on the susceptibility of NHPs to tau-related disorders (Walker and Jucker, 2017). It is notable that marmosets and lemurs, unlike Old World monkeys, did not present tau inclusions with age, intracerebral injections of AD brain homogenates, or fibrillary Aβ. This finding underscores that differences in tau sequence across NHP species, albeit small, may affect pathophysiology and need to be considered for model development.
Accumulated data show that investigators cannot rely on identifying enough affected old NHPs to conduct statistically powered studies. As an alternative, intracerebral injection of either brain homogenates, protein extracts, or viral vectors have been utilized to locally increase the protein burden as a shortcut to induce pathology; attempts to transgenic modeling also applied the concept of increase protein burden. Most reports aimed to develop AD models by increasing Aβ burden. The exceptions utilized brain tissue from PSP patients (Darricau et al., 2024; Darricau et al., 2022) or viral vectors encoding for multiple tau mutations (Beckman et al., 2021; Beckman et al., 2024; Jiang et al., 2024). As understanding of tauopathies deepens, the models as well as the methods of evaluation need to be refined. In that regard, new models focused on increasing specific strains of tau burden resembling different primary tauopathies would be beneficial to the field.
Based on our review of the literature, we identified a number of parameters that could help evaluate NHP models of tauopathies as well as answer whether some NHPs can spontaneously develop tauopathies, especially AD. First, if identification of AT8+ NFTs is the standard for Braak staging in human disease (Braak et al., 2006), identification of tauopathy in NHPs should include AT8 immunohistochemistry. Second, when reporting AT8-ir pathology, a systematic evaluation of multiple regions in all study subjects, specifically in the transentorhinal, limbic, and isocortical regions is recommended; ideally a table should be presented to depict pathological burden per region for each animal. Quantification of filamentous tau inclusions and knowledge of their ultrastructure (e.g., PHFs) would help provide clarity in NHP studies. Third, reports of AD-like tau pathology would benefit from applying similar rigor of evaluation for detecting Aβ pathology (e.g., Thal scoring). Fourth, evaluation of neurodegeneration patterns, cell type affected and expression of 3R- and 4R-tau, alpha-synuclein and TDP-43, between others, would facilitate differential diagnoses. Fifth, in vivo behavioral, imaging, and biomarker data are needed to inform the postmortem analyses with clinically relevant measures to ultimately diagnose NHPs with tau-related diseases.
8.2 Emerging paradigms
Advances in biotechnology present opportunities for creating a new generation of NHP models of tauopathies. For example, viral vectors that can cross the blood brain barrier, such as AAV-CAP-B10 (Goertsen et al., 2022), could be used for introducing mutated MAPT genes without the need for intracerebral injections.
As an alternative to transgenesis, genome editing is envisioned to generate animal models that genocopy and phenocopy genetic disease conditions (Schmidt et al., 2022). Rizzo et al. (2023) have reported the successful development of marmosets carrying PSEN1 point mutations C410Y and A426P by CRISPR/Cas9. The group predicts that the mutant marmosets will display Aβ accumulation detectable by PET by 4 years of age, equivalent to a 32-year-old human. The future results of this study may provide clues on whether marmosets develop true neurodegeneration with Aβ and tauopathy.
Targeted genotyping of NHPs with abnormal phenotypes or systematic genotyping of NHP colonies could help identify animals carrying mutations of interest. For example, a collaborative effort from several primate research centers reported whole genome sequencing of 84 common marmosets that identified 27 total variants with a clinical significance of pathogenic and/or likely pathogenic (Harris et al., 2023). Some of these variants occurred in AD risk genes, including a stop-gain variant in ABCA7. Whole genome sequencing of NHP colonies is pragmatic; it would inform whether coding and non-coding single nucleotide polymorphisms are conserved between humans and NHPs. Whole genome datasets are available from multiple NHP species (Kuderna et al., 2023; Warren et al., 2020), yet there are a lack of genome-wide association studies linking genetic variants to tau burden and phosphorylation. Furthermore, whole genome sequencing of NHP colonies can identify animals carrying endogenous mutations, which would allow investigators to bypass genetic manipulation for creating models of neurodegeneration and interrogate animals for bona fide pathology. At the Wisconsin National Primate Research Center, we have used this approach in our monkey colonies and identified a family of rhesus macaques carrying a heterozygous MAPT R406W mutation. This point mutation, occurring in exon 13, is autosomal dominant in human FTDP-17 and dramatically reduces microtubule binding ability of tau (Dayanandan et al., 1999). Ongoing studies in our lab aim to phenotype these animals using a comprehensive battery of behavioral, imaging, and biochemical measures.
8.3 The ethical challenge of modeling tauopathies in NHPs
AD and FTD are tragic diseases that deeply affect patients and their families. The dementia field knows what is needed to advance patient care: early and accurate diagnoses, neuroprotective therapies, and better symptom management, to name a few. Can we afford not to do animal research? As our closest relatives, NHPs can provide answers to help patients. Yet the decision to study these disorders in NHPs must balance the harm vs. benefit to be gained.
A true model of tauopathy may induce behaviors, such as intense anxiety, that require appropriate care to ensure animal health. Therefore, a partnership between researchers and the veterinarian care team is essential. Veterinarians and animal technicians can provide insight into NHP spontaneous activities and managing extreme behaviors with enrichment opportunities and/or medications defined by individual cases. The housing of these animals may require additional steps to ensure a stable environment both within the animal enclosure as well as the animal room or pen; this should be thoroughly discussed with the animal care team. In addition to compatibility between subjects, evaluation of new pairings or social housing must include the emergence or extinction of abnormal behaviors (e.g., stereotypies, self-injury behaviors). Breeding of NHP mutation carriers is envisioned to produce cohorts of affected animals; its success depends on expert pedigree pairing for mating, as well as to protect offspring. In vitro fertilization with gametes collected from mutation carriers can facilitate the expansion of a colony but may be limited by veterinarian expertise and institutional commitment to the NHP colony.
NHPs are a limited resource, and access to monkeys is becoming increasingly difficult, which is compounded by the rise in regulatory burden and cost of NHP research. In this context, prioritization of models to be developed and expanded should emphasize their clinical relevance. Tauopathies require time for phenotypic emergence, thus, care must be taken to ensure animal wellbeing and the use of minimally invasive methods of evaluation that will lead to the production of faithful, replicable results. In this context, comprehensive multimodal blind analyses and properly powered studies with aged- and sex-matched control population standards will provide the answers needed to ultimately advance dementia care.
9 Conclusion
The study of tauopathies in animals is essential to understand the interaction of multiple biological factors that lead to pathological accumulation of tau, as well as to identify and validate therapeutic targets. NHPs can provide unique insight due to their complex behavior and neurobiology and the similarity of the tau protein across humans and NHPs. Applying rigorous methods that mirror human studies while caring for the animals’ wellbeing will be critical for producing meaningful studies of tauopathies in NHPs.
Author contributions
JC: Writing – original draft, Writing – review & editing. ME: Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This research was supported by NIH awards R61/R33 NS115102, R01NS124857, P51OD011106, F31AG084303, the Cellular and Molecular Pathology Graduate Program T32 GM081061, and the Rainwater Foundation.
Acknowledgments
We thank Dr. Shariar Salamat for providing the images of human tauopathies utilized in Figure 2.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Generative AI statement
The authors declare that no Gen AI was used in the creation of this manuscript.
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References
Abbott, D. H., Barnett, D. K., Colman, R. J., Yamamoto, M. E., and Schultz-Darken, N. J. (2003). Aspects of common marmoset basic biology and life history important for biomedical research. Comp. Med. 53, 339–350. doi: 10.1016/B978-0-12-811829-0.00001-7
Alquezar, C., Arya, S., and Kao, A. W. (2020). Tau post-translational modifications: dynamic transformers of tau function, degradation, and aggregation. Front. Neurol. 11:595532. doi: 10.3389/fneur.2020.595532
Amos, L. A. (2004). Microtubule structure and its stabilisation. Org. Biomol. Chem. 2, 2153–2160. doi: 10.1039/b403634d
Andreadis, A. (2005). Tau gene alternative splicing: expression patterns, regulation and modulation of function in normal brain and neurodegenerative diseases. Biochim. Biophys. Acta 1739, 91–103. doi: 10.1016/j.bbadis.2004.08.010
Andreadis, A. (2013). Tau splicing and the intricacies of dementia. J. Cell. Physiol. 227, 1220–1225. doi: 10.1002/jcp.22842
Arienti, F., Lazzeri, G., Vizziello, M., Monfrini, E., Bresolin, N., Saetti, M. C., et al. (2021). Unravelling genetic factors underlying corticobasal syndrome: a systematic review. Cells 10:171. doi: 10.3390/cells10010171
Augustinack, J. C., Schneider, A., Mandelkow, E. M., and Hyman, B. T. (2002). Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease. Acta Neuropathol. 103, 26–35. doi: 10.1007/s004010100423
Avila, J., Jiménez, J. S., Sayas, C. L., Bolós, M., Zabala, J. C., Rivas, G., et al. (2016). Tau structures. Front. Aging Neurosci. 8:262. doi: 10.3389/fnagi.2016.00262
Baker, H. F., Ridley, R. M., Duchen, L. W., Crow, T. J., and Bruton, C. J. (1993). Evidence for the experimental transmission of cerebral beta-amyloidosis to primates. Int. J. Exp. Pathol. 74, 441–454.
Bang, J., Spina, S., and Miller, B. L. (2015). Frontotemporal dementia. Lancet 386, 1672–1682. doi: 10.1016/S0140-6736(15)00461-4
Barnes, C. A., Permenter, M. R., Vogt, J. A., Chen, K., and Beach, T. G. (2024). Human Alzheimer's disease ATN/ABC staging applied to aging Rhesus macaque brains: association with cognition and MRI-based regional Gray matter volume. J. Comp. Neurol. 532:e25670. doi: 10.1002/cne.25670
Beber, B. C., and Chaves, M. L. F. (2013). Evaluation of patients with behavioral and cognitive complaints: misdiagnosis in frontotemporal dementia and Alzheimer's disease. Dement Neuropsychol 7, 60–65. doi: 10.1590/S1980-57642013DN70100010
Beckman, D., Chakrabarty, P., Ott, S., Dao, A., Zhou, E., Janssen, W. G., et al. (2021). A novel tau-based rhesus monkey model of Alzheimer's pathogenesis. Alzheimers Dement. 17, 933–945. doi: 10.1002/alz.12318
Beckman, D., Diniz, G. B., Ott, S., Hobson, B., Chaudhari, A. J., Muller, S., et al. (2024). Temporal progression of tau pathology and neuroinflammation in a rhesus monkey model of Alzheimer's disease. Alzheimers Dement. 20, 5198–5219. doi: 10.1002/alz.13868
Binder, L. I., Guillozet-Bongaarts, A. L., Garcia-Sierra, F., and Berry, R. W. (2005). Tau, tangles, and Alzheimer's disease. Biochim. Biophys. Acta 1739, 216–223. doi: 10.1016/j.bbadis.2004.08.014
Bocchetta, M., Cardoso, M. J., Cash, D. M., Ourselin, S., Warren, J. D., and Rohrer, J. D. (2016). Patterns of regional cerebellar atrophy in genetic frontotemporal dementia. Neuroimage Clin 11, 287–290. doi: 10.1016/j.nicl.2016.02.008
Boeve, B. F., and Hutton, M. (2008). Refining frontotemporal dementia with parkinsonism linked to chromosome 17: introducing FTDP-17 (MAPT) and FTDP-17 (PGRN). Arch. Neurol. 65, 460–464. doi: 10.1001/archneur.65.4.460
Bons, N., Jallageas, V., Mestre-Frances, N., Silhol, S., Petter, A., and Delacourte, A. (1995a). Microcebus murinus, a convenient laboratory animal for the study of Alzheimer's disease. Alzheimer's Res. 1, 83–87.
Bons, N., Jallageas, V., Silhol, S., Mestre-Frances, N., Petter, A., and Delacourte, A. (1995b). Immunocytochemical characterization of tau proteins during cerebral aging of the lemurian primate Microcebus murinus. C. R. Acad. Sci. III 318, 741–747.
Bons, N., Mestre, N., and Petter, A. (1992). Senile plaques and neurofibrillary changes in the brain of an aged lemurian primate, Microcebus murinus. Neurobiol. Aging 13, 99–105. doi: 10.1016/0197-4580(92)90016-q
Bouras, C., Hof, P. R., and Morrison, J. H. (1993). Neurofibrillary tangle densities in the hippocampal formation in a non-demented population define subgroups of patients with differential early pathologic changes. Neurosci. Lett. 153, 131–135. doi: 10.1016/0304-3940(93)90305-5
Braak, H., Alafuzoff, I., Arzberger, T., Kretzschmar, H., and Del Tredici, K. (2006). Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 112, 389–404. doi: 10.1007/s00401-006-0127-z
Braak, H., and Braak, E. (1991). Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259. doi: 10.1007/BF00308809
Bussy, A., Levy, J. P., Best, T., Patel, R., Cupo, L., and Van Langenhove, T. (2023). Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia. Hum. Brain Mapp. 44, 2684–2700. doi: 10.1002/hbm.26220
Carlyle, B. C., Nairn, A. C., Wang, M., Yang, Y., Jin, L. E., Simen, A. A., et al. (2014). cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex. Proc. Natl. Acad. Sci. USA 111, 5036–5041. doi: 10.1073/pnas.1322360111
Chan, A. W. S., Cho, I. K., Li, C. X., Zhang, X., Patel, S., Rusnak, R., et al. (2022). Cerebral aβ deposition in an aβ-precursor protein-transgenic rhesus monkey. Aging Brain 2:44. doi: 10.1016/j.nbas.2022.100044
Chen, D., Drombosky, K. W., Hou, Z., Sari, L., Kashmer, O. M., Ryder, B. D., et al. (2019). Tau local structure shields an amyloid-forming motif and controls aggregation propensity. Nat. Commun. 10:2493. doi: 10.1038/s41467-019-10355-1
Chen, X., and Jiang, H. (2019). Tau as a potential therapeutic target for ischemic stroke. Aging 11, 12827–12843. doi: 10.18632/aging.102547
Chen, Y., Kumfor, F., Landin-Romero, R., Irish, M., and Piguet, O. (2019). The cerebellum in frontotemporal dementia: a Meta-analysis of neuroimaging studies. Neuropsychol. Rev. 29, 450–464. doi: 10.1007/s11065-019-09414-7
Chung, D. C., Roemer, S., Petrucelli, L., and Dickson, D. W. (2021). Cellular and pathological heterogeneity of primary tauopathies. Mol. Neurodegener. 16:57. doi: 10.1186/s13024-021-00476-x
Cody, K. A., Langhough, R. E., Zammit, M. D., Clark, L., Chin, N., Christian, B. T., et al. (2024). Characterizing brain tau and cognitive decline along the amyloid timeline in Alzheimer's disease. Brain 147, 2144–2157. doi: 10.1093/brain/awae116
Corey, T. M., Illanes, O., Lawrence, M., Perez, S. E., Liddie, S., and Callanan, J. J. (2023). Naturally occurring histological findings and Alzheimer's-like pathology in the brain of aging African green monkeys (Chlorocebus sabaeus). J. Comp. Neurol. 531, 1276–1298. doi: 10.1002/cne.25494
Cramer, P. E., Gentzel, R. C., Tanis, K. Q., Vardigan, J., Wang, Y., Connolly, B., et al. (2018). Aging African green monkeys manifest transcriptional, pathological, and cognitive hallmarks of human Alzheimer's disease. Neurobiol. Aging 64, 92–106. doi: 10.1016/j.neurobiolaging.2017.12.011
Crary, J. F., Trojanowski, J. Q., Schneider, J. A., Abisambra, J. F., Abner, E. L., Alafuzoff, I., et al. (2014). Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 128, 755–766. doi: 10.1007/s00401-014-1349-0
Crimins, J. L., Puri, R., Calakos, K. C., Yuk, F., Janssen, W. G. M., Hara, Y., et al. (2019). Synaptic distributions of pS214-tau in rhesus monkey prefrontal cortex are associated with spine density, but not with cognitive decline. J. Comp. Neurol. 527, 856–873. doi: 10.1002/cne.24576
Darricau, M., Dou, C., Kinet, R., Zhu, T., Zhou, L., Li, X., et al. (2024). Tau seeds from Alzheimer's disease brains trigger tau spread in macaques while oligomeric-aβ mediates pathology maturation. Alzheimers Dement. 20, 1894–1912. doi: 10.1002/alz.13604
Darricau, M., Katsinelos, T., Raschella, F., Milekovic, T., Crochemore, L., Li, Q., et al. (2022). Tau seeds from patients induce progressive supranuclear palsy pathology and symptoms in primates. Brain 146:awac428. doi: 10.1093/brain/awac428
Darusman, H. S., Gjedde, A., Sajuthi, D., Schapiro, S. J., Kalliokoski, O., Kristianingrum, Y. P., et al. (2014). Amyloid Beta1-42 and the phoshorylated tau threonine 231 in brains of aged cynomolgus monkeys (Macaca fascicularis). Front. Aging Neurosci. 6:313. doi: 10.3389/fnagi.2014.00313
Datta, D., Leslie, S. N., Wang, M., Morozov, Y. M., Yang, S., Mentone, S., et al. (2021). Age-related calcium dysregulation linked with tau pathology and impaired cognition in non-human primates. Alzheimers Dement. 17, 920–932. doi: 10.1002/alz.12325
Dayanandan, R., Van Slegtenhorst, M., Mack, T. G., Ko, L., Yen, S. H., Leroy, K., et al. (1999). Mutations in tau reduce its microtubule binding properties in intact cells and affect its phosphorylation. FEBS Lett. 446, 228–232. doi: 10.1016/s0014-5793(99)00222-7
Dehmelt, L., and Halpain, S. (2005). The MAP2/tau family of microtubule-associated proteins. Genome Biol. 6:204. doi: 10.1186/gb-2004-6-1-204
Del Tredici, K., and Braak, H. (2020). To stage, or not to stage. Curr. Opin. Neurobiol. 61, 10–22. doi: 10.1016/j.conb.2019.11.008
Ducharme, S., Dols, A., Laforce, R., Devenney, E., Kumfor, F., van den Stock, J., et al. (2020). Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders. Brain 143, 1632–1650. doi: 10.1093/brain/awaa018
Dujardin, S., Colin, M., and Buée, L. (2015). Invited review: animal models of tauopathies and their implications for research/translation into the clinic. Neuropathol. Appl. Neurobiol. 41, 59–80. doi: 10.1111/nan.12200
Edler, M. K., Sherwood, C. C., Meindl, R. S., Hopkins, W. D., Ely, J. J., Erwin, J., et al. (2017). Aged chimpanzees exhibit pathologic hallmarks of Alzheimer's disease. Neurobiol. Aging 59, 107–120. doi: 10.1016/j.neurobiolaging.2017.07.006
Edwards, G., Zhao, J., Dash, P. K., Soto, C., and Moreno-Gonzalez, I. (2020). Traumatic brain injury induces tau aggregation and spreading. J. Neurotrauma 37, 80–92. doi: 10.1089/neu.2018.6348
Elfenbein, H. A., Rosen, R. F., Stephens, S. L., Switzer, R. C., Smith, Y., Pare, J., et al. (2007). Cerebral beta-amyloid angiopathy in aged squirrel monkeys. Histol. Histopathol. 22, 155–167. doi: 10.14670/HH-22.155
Emborg, M. E., Ma, S. Y., Mufson, E. J., Levey, A. I., Taylor, M. D., Brown, W. D., et al. (1998). Age-related declines in nigral neuronal function correlate with motor impairments in rhesus monkeys. J. Comp. Neurol. 401, 253–265. doi: 10.1002/(SICI)1096-9861(19981116)401:2<>3.0.CO;2-X
Ferrer, I., Santpere, G., and van Leeuwen, F. W. (2008). Argyrophilic grain disease. Brain 131, 1416–1432. doi: 10.1093/brain/awm305
Forny-Germano, L., Lyra e Silva, N. M., Batista, A. F., Brito-Moreira, J., Gralle, M., Boehnke, S. E., et al. (2014). Alzheimer's disease-like pathology induced by amyloid-β oligomers in nonhuman primates. J. Neurosci. 34, 13629–13643. doi: 10.1523/JNEUROSCI.1353-14.2014
Freire-Cobo, C., Rothwell, E. S., Varghese, M., Edwards, M., Janssen, W. G. M., Lacreuse, A., et al. (2023). Neuronal vulnerability to brain aging and neurodegeneration in cognitively impaired marmoset monkeys (Callithrix jacchus). Neurobiol. Aging 123, 49–62. doi: 10.1016/j.neurobiolaging.2022.12.001
Friedrich, M. G., Skora, A., Hancock, S. E., Mitchell, T. W., Else, P. L., and Truscott, R. J. W. (2021). Tau is truncated in five regions of the Normal adult human brain. Int. J. Mol. Sci. 22:3521. doi: 10.3390/ijms22073521
Gambardella, J. C., Schoephoerster, W., Bondarenko, V., Yandell, B. S., and Emborg, M. E. (2023). Expression of tau and phosphorylated tau in the brain of normal and hemiparkinsonian rhesus macaques. J. Comp. Neurol. 531, 1198–1216. doi: 10.1002/cne.25490
García-Sierra, F., Ghoshal, N., Quinn, B., Berry, R. W., and Binder, L. I. (2003). Conformational changes and truncation of tau protein during tangle evolution in Alzheimer's disease. J. Alzheimers Dis. 5, 65–77. doi: 10.3233/jad-2003-5201
Gary, C., Lam, S., Hérard, A. S., Koch, J. E., Petit, F., Gipchtein, P., et al. (2019). Encephalopathy induced by Alzheimer brain inoculation in a non-human primate. Acta Neuropathol. Commun. 7:126. doi: 10.1186/s40478-019-0771-x
Gearing, M., Rebeck, G. W., Hyman, B. T., Tigges, J., and Mirra, S. S. (1994). Neuropathology and apolipoprotein E profile of aged chimpanzees: implications for Alzheimer disease. Proc. Natl. Acad. Sci. USA 91, 9382–9386. doi: 10.1073/pnas.91.20.9382
Gearing, M., Tigges, J., Mori, H., and Mirra, S. S. (1997). Beta-amyloid (A beta) deposition in the brains of aged orangutans. Neurobiol. Aging 18, 139–146. doi: 10.1016/s0197-4580(97)00012-2
Geng, J., Xia, L., Li, W., and Dou, F. (2015). The C-terminus of tau protein plays an important role in its stability and toxicity. J. Mol. Neurosci. 55, 251–259. doi: 10.1007/s12031-014-0314-7
Geula, C., Nagykery, N., and Wu, C. K. (2002). Amyloid-beta deposits in the cerebral cortex of the aged common marmoset (Callithrix jacchus): incidence and chemical composition. Acta Neuropathol. 103, 48–58. doi: 10.1007/s004010100429
Geula, C., Wu, C. K., Saroff, D., Lorenzo, A., Yuan, M., and Yankner, B. A. (1998). Aging renders the brain vulnerable to amyloid beta-protein neurotoxicity. Nat. Med. 4, 827–831. doi: 10.1038/nm0798-827
Giannakopoulos, P., Silhol, S., Jallageas, V., Mallet, J., Bons, N., Bouras, C., et al. (1997). Quantitative analysis of tau protein-immunoreactive accumulations and beta amyloid protein deposits in the cerebral cortex of the mouse lemur, Microcebus murinus. Acta Neuropathol. 94, 131–139. doi: 10.1007/s004010050684
Gil, M. J., Manzano, M. S., Cuadrado, M. L., Fernández, C., Góméz, E., Matesanz, C., et al. (2018). Argyrophilic grain pathology in frontotemporal lobar degeneration: demographic, clinical, neuropathological, and genetic features. J. Alzheimers Dis. 63, 1109–1117. doi: 10.3233/JAD-171115
Goertsen, D., Flytzanis, N. C., Goeden, N., Chuapoco, M. R., Cummins, A., Chen, Y., et al. (2022). AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset. Nat. Neurosci. 25, 106–115. doi: 10.1038/s41593-021-00969-4
Gonzales, L. A., Benefit, B. R., McCrossin, M. L., and Spoor, F. (2015). Cerebral complexity preceded enlarged brain size and reduced olfactory bulbs in Old World monkeys. Nat. Commun. 6:7580. doi: 10.1038/ncomms8580
Goode, B. L., and Feinstein, S. C. (1994). Identification of a novel microtubule binding and assembly domain in the developmentally regulated inter-repeat region of tau. J. Cell Biol. 124, 769–782. doi: 10.1083/jcb.124.5.769
Gu, J., Xu, W., Jin, N., Li, L., Zhou, Y., Chu, D., et al. (2020). Truncation of tau selectively facilitates its pathological activities. J. Biol. Chem. 295, 13812–13828. doi: 10.1074/jbc.RA120.012587
Guillozet-Bongaarts, A. L., Glajch, K. E., Libson, E. G., Cahill, M. E., Bigio, E., Berry, R. W., et al. (2007). Phosphorylation and cleavage of tau in non-AD tauopathies. Acta Neuropathol. 113, 513–520. doi: 10.1007/s00401-007-0209-6
Harris, R. A., Raveendran, M., Warren, W., LaDeana, H. W., Tomlinson, C., Graves-Lindsay, T., et al. (2023). Whole genome analysis of SNV and indel polymorphism in common marmosets. Genes 14:185. doi: 10.3390/genes14122185
Härtig, W., Klein, C., Brauer, K., Schüppel, K. F., Arendt, T., Brückner, G., et al. (2000). Abnormally phosphorylated protein tau in the cortex of aged individuals of various mammalian orders. Acta Neuropathol. 100, 305–312. doi: 10.1007/s004010000183
Hefti, M. M., Farrell, K., Kim, S., Bowles, K. R., Fowkes, M. E., Raj, T., et al. (2018). High-resolution temporal and regional mapping of MAPT expression and splicing in human brain development. PLoS One 13:e0195771. doi: 10.1371/journal.pone.0195771
Hohenbrink, S., Zimmermann, E., and Radespiel, U. (2015). Need for speed: sexual maturation precedes social maturation in gray mouse lemurs. Am. J. Primatol. 77, 1049–1059. doi: 10.1002/ajp.22440
Holzer, M., Craxton, M., Jakes, R., Arendt, T., and Goedert, M. (2004). Tau gene (MAPT) sequence variation among primates. Gene 341, 313–322. doi: 10.1016/j.gene.2004.07.013
Hopkins, W. D., Mareno, M. C., Neal Webb, S. J., Schapiro, S. J., Raghanti, M. A., and Sherwood, C. C. (2021). Age-related changes in chimpanzee (Pan troglodytes) cognition: cross-sectional and longitudinal analyses. Am. J. Primatol. 83:e23214. doi: 10.1002/ajp.23214
Huhe, H., Shapley, S. M., Duong, D. M., Wu, F., Ha, S.-K., Choi, S.-H., et al. (2024). Marmosets as model systems for the study of Alzheimer's disease and related dementias: substantiation of physiological tau 3R and 4R isoform expression and phosphorylation. Alzheimers Dement. 21:e14366. doi: 10.1002/alz.14366
Irwin, D. J., Brettschneider, J., McMillan, C. T., Cooper, F., Olm, C., Arnold, S. E., et al. (2016). Deep clinical and neuropathological phenotyping of pick disease. Ann. Neurol. 79, 272–287. doi: 10.1002/ana.24559
Jester, H. M., Gosrani, S. P., Ding, H., Zhou, X., Ko, M. C., and Ma, T. (2022). Characterization of early Alzheimer's disease-like pathological alterations in non-human Primates with aging: A pilot study. J. Alzheimers Dis. 88, 957–970. doi: 10.3233/JAD-215303
Jiang, Z., Wang, J., Qin, Y., Liu, S., Luo, B., Bai, F., et al. (2024). A nonhuman primate model with Alzheimer's disease-like pathology induced by hippocampal overexpression of human tau. Alzheimers Res. Ther. 16:22. doi: 10.1186/s13195-024-01392-0
Kadavath, H., Hofele, R. V., Biernat, J., Kumar, S., Tepper, K., Urlaub, H., et al. (2015). Tau stabilizes microtubules by binding at the interface between tubulin heterodimers. Proc. Natl. Acad. Sci. USA 112, 7501–7506. doi: 10.1073/pnas.1504081112
Kellogg, E. H., Hejab, N. M. A., Poepsel, S., Downing, K. H., DiMaio, F., and Nogales, E. (2018). Near-atomic model of microtubule-tau interactions. Science 360, 1242–1246. doi: 10.1126/science.aat1780
Kiatipattanasakul, W., Nakayama, H., Yongsiri, S., Chotiapisitkul, S., Nakamura, S., Kojima, H., et al. (2000). Abnormal neuronal and glial argyrophilic fibrillary structures in the brain of an aged albino cynomolgus monkey (Macaca fascicularis). Acta Neuropathol. 100, 580–586. doi: 10.1007/s004010000215
Kimura, T., Ishiguro, K., and Hisanaga, S. (2014). Physiological and pathological phosphorylation of tau by Cdk5. Front. Mol. Neurosci. 7:65. doi: 10.3389/fnmol.2014.00065
Kimura, N., Nakamura, S., Goto, N., Narushima, E., Hara, I., Shichiri, S., et al. (2001). Senile plaques in an aged western lowland gorilla. Exp. Anim. 50, 77–81. doi: 10.1538/expanim.50.77
Kimura, N., Tanemura, K., Nakamura, S., Takashima, A., Ono, F., Sakakibara, I., et al. (2003). Age-related changes of Alzheimer's disease-associated proteins in cynomolgus monkey brains. Biochem. Biophys. Res. Commun. 310, 303–311. doi: 10.1016/j.bbrc.2003.09.012
Kovacs, G. G. (2015). “Tauopathies” in Neuropathology of neurodegenerative diseases a practical guide. ed. G. G. Kovacs (Cambridge: Cambridge University Press), 109–148.
Kovacs, G. G., Lukic, M. J., Irwin, D. J., Arzberger, T., Respondek, G., Lee, E. B., et al. (2020). Distribution patterns of tau pathology in progressive supranuclear palsy. Acta Neuropathol. 140, 99–119. doi: 10.1007/s00401-020-02158-2
Kovacs, G. G., Milenkovic, I., Wöhrer, A., Höftberger, R., Gelpi, E., Haberler, C., et al. (2013). Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series. Acta Neuropathol. 126, 365–384. doi: 10.1007/s00401-013-1157-y
Kraska, A., Dorieux, O., Picq, J. L., Petit, F., Bourrin, E., Chenu, E., et al. (2011). Age-associated cerebral atrophy in mouse lemur primates. Neurobiol. Aging 32, 894–906. doi: 10.1016/j.neurobiolaging.2009.05.018
Kuderna, L. F. K., Gao, H., Janiak, M. C., Kuhlwilm, M., Orkin, J. D., Bataillon, T., et al. (2023). A global catalog of whole-genome diversity from 233 primate species. Science 380, 906–913. doi: 10.1126/science.abn7829
Kuroki, K., Uchida, K., Kiatipattanasakul, W., Nakamura, S.-i., Yamaguchi, R., Nakayama, H., et al. (1997). Immunohistochemical detection of tau protein in various non-human animal brains. Neuropathology 17, 174–180. doi: 10.1111/j.1440-1789.1997.tb00034.x
Latimer, C. S., Shively, C. A., Keene, C. D., Jorgensen, M. J., Andrews, R. N., Register, T. C., et al. (2019). A nonhuman primate model of early Alzheimer's disease pathologic change: implications for disease pathogenesis. Alzheimers Dement. 15, 93–105. doi: 10.1016/j.jalz.2018.06.3057
Lee, D. S., Kang, Y. H. R., Ruiz-Lambides, A. V., and Higham, J. P. (2021). The observed pattern and hidden process of female reproductive trajectories across the life span in a non-human primate. J. Anim. Ecol. 90, 2901–2914. doi: 10.1111/1365-2656.13590
Lee, G., and Leugers, C. J. (2012). Tau and tauopathies. Prog. Mol. Biol. Transl. Sci. 107, 263–293. doi: 10.1016/B978-0-12-385883-2.00004-7
Lemere, C. A., Beierschmitt, A., Iglesias, M., Spooner, E. T., Bloom, J. K., Leverone, J. F., et al. (2004). Alzheimer's disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet. Am. J. Pathol. 165, 283–297. doi: 10.1016/s0002-9440(10)63296-8
Lemere, C. A., Oh, J., Stanish, H. A., Peng, Y., Pepivani, I., Fagan, A. M., et al. (2008). Cerebral amyloid-beta protein accumulation with aging in cotton-top tamarins: a model of early Alzheimer's disease? Rejuvenation Res. 11, 321–332. doi: 10.1089/rej.2008.0677
Leslie, S. N., Kanyo, J., Datta, D., Wilson, R. S., Zeiss, C., Duque, A., et al. (2021). Simple, single-shot phosphoproteomic analysis of heat-stable tau identifies age-related changes in pS235- and pS396-tau levels in non-human primates. Front. Aging Neurosci. 13:767322. doi: 10.3389/fnagi.2021.767322
Liu, F., and Gong, C. X. (2008). Tau exon 10 alternative splicing and tauopathies. Mol. Neurodegener. 3:8. doi: 10.1186/1750-1326-3-8
Mandelkow, E., von Bergen, M., Biernat, J., and Mandelkow, E. (2007). Structural principles of tau and the paired helical filaments of Alzheimer's disease. Brain Pathol. 17, 83–90. doi: 10.1111/j.1750-3639.2007.00053.x
Martin, L., Latypova, X., Wilson, C. M., Magnaudeix, A., Perrin, M. L., Yardin, C., et al. (2013). Tau protein kinases: involvement in Alzheimer's disease. Ageing Res. Rev. 12, 289–309. doi: 10.1016/j.arr.2012.06.003
Martine, P., and Aude, A. (2022). Parental age at conception on mouse lemur's offspring longevity: sex-specific maternal effects. PLoS One 17:e0265783. doi: 10.1371/journal.pone.0265783
McKibben, K. M., and Rhoades, E. (2019). Independent tubulin binding and polymerization by the proline-rich region of tau is regulated by tau's N-terminal domain. J. Biol. Chem. 294, 19381–19394. doi: 10.1074/jbc.RA119.010172
Metzler, L. A. P., Metzger, J. M., Gerred, K. J., Emborg, M. E., and Kapoor, A. (2025). Expression patterns of blood-based biomarkers of neurodegeneration and inflammation across adulthood in rhesus macaques. Exp. Gerontol. 203:112736. doi: 10.1016/j.exger.2025.112736
Mirbaha, H., Chen, D., Morazova, O. A., Ruff, K. M., Sharma, A. M., Liu, X., et al. (2018). Inert and seed-competent tau monomers suggest structural origins of aggregation. eLife 7:36584. doi: 10.7554/eLife.36584
Mondragón-Rodríguez, S., Basurto-Islas, G., Santa-Maria, I., Mena, R., Binder, L. I., Avila, J., et al. (2008). Cleavage and conformational changes of tau protein follow phosphorylation during Alzheimer's disease. Int. J. Exp. Pathol. 89, 81–90. doi: 10.1111/j.1365-2613.2007.00568.x
Moore, T. L., Killiany, R. J., Herndon, J. G., Rosene, D. L., and Moss, M. B. (2006). Executive system dysfunction occurs as early as middle-age in the rhesus monkey. Neurobiol. Aging 27, 1484–1493. doi: 10.1016/j.neurobiolaging.2005.08.004
Morris, J. C., McKeel, D. W., Storandt, M., Rubin, E. H., Price, J. L., Grant, E. A., et al. (1991). Very mild Alzheimer's disease: informant-based clinical, psychometric, and pathologic distinction from normal aging. Neurology 41, 469–478. doi: 10.1212/wnl.41.4.469
Ndung'u, M., Härtig, W., Wegner, F., Mwenda, J. M., Low, R. W., Akinyemi, R. O., et al. (2012). Cerebral amyloid β(42) deposits and microvascular pathology in ageing baboons. Neuropathol. Appl. Neurobiol. 38, 487–499. doi: 10.1111/j.1365-2990.2011.01246.x
Nelson, P. T., Abner, E. L., Schmitt, F. A., Kryscio, R. J., Jicha, G. A., Santacruz, K., et al. (2009). Brains with medial temporal lobe neurofibrillary tangles but no neuritic amyloid plaques are a diagnostic dilemma but may have pathogenetic aspects distinct from Alzheimer disease. J. Neuropathol. Exp. Neurol. 68, 774–784. doi: 10.1097/NEN.0b013e3181aacbe9
Nelson, P. T., Stefansson, K., Gulcher, J., and Saper, C. B. (1996). Molecular evolution of tau protein: implications for Alzheimer's disease. J. Neurochem. 67, 1622–1632. doi: 10.1046/j.1471-4159.1996.67041622.x
Oikawa, N., Kimura, N., and Yanagisawa, K. (2010). Alzheimer-type tau pathology in advanced aged nonhuman primate brains harboring substantial amyloid deposition. Brain Res. 1315, 137–149. doi: 10.1016/j.brainres.2009.12.005
Okabayashi, S., Shimozawa, N., Yasutomi, Y., Yanagisawa, K., and Kimura, N. (2015). Diabetes mellitus accelerates aβ pathology in brain accompanied by enhanced GAβ generation in nonhuman primates. PLoS One 10:e0117362. doi: 10.1371/journal.pone.0117362
Paspalas, C. D., Carlyle, B. C., Leslie, S., Preuss, T. M., Crimins, J. L., Huttner, A. J., et al. (2018). The aged rhesus macaque manifests Braak stage III/IV Alzheimer's-like pathology. Alzheimers Dement. 14, 680–691. doi: 10.1016/j.jalz.2017.11.005
Paterno, G., Bell, B. M., Gorion, K. M., Prokop, S., and Giasson, B. I. (2022). Reassessment of neuronal tau distribution in adult human brain and implications for tau pathobiology. Acta Neuropathol. Commun. 10:94. doi: 10.1186/s40478-022-01394-9
Perez, S. E., Raghanti, M. A., Hof, P. R., Kramer, L., Ikonomovic, M. D., Lacor, P. N., et al. (2013). Alzheimer's disease pathology in the neocortex and hippocampus of the western lowland gorilla (Gorilla gorilla gorilla). J. Comp. Neurol. 521, 4318–4338. doi: 10.1002/cne.23428
Perez, S. E., Sherwood, C. C., Cranfield, M. R., Erwin, J. M., Mudakikwa, A., Hof, P. R., et al. (2016). Early Alzheimer's disease-type pathology in the frontal cortex of wild mountain gorillas (Gorilla beringei beringei). Neurobiol. Aging 39, 195–201. doi: 10.1016/j.neurobiolaging.2015.12.017
Phillips, K. A., Bales, K. L., Capitanio, J. P., Conley, A., Czoty, P. W., Hopkins, W. D., et al. (2014). Why primate models matter. Am. J. Primatol. 76, 801–827. doi: 10.1002/ajp.22281
Pittet, F., Johnson, C., and Hinde, K. (2017). Age at reproductive debut: developmental predictors and consequences for lactation, infant mass, and subsequent reproduction in rhesus macaques (Macaca mulatta). Am. J. Phys. Anthropol. 164, 457–476. doi: 10.1002/ajpa.23286
Podlisny, M. B., Tolan, D. R., and Selkoe, D. J. (1991). Homology of the amyloid beta protein precursor in monkey and human supports a primate model for beta amyloidosis in Alzheimer's disease. Am. J. Pathol. 138, 1423–1435.
Price, J. L., Davis, P. B., Morris, J. C., and White, D. L. (1991). The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer's disease. Neurobiol. Aging 12, 295–312. doi: 10.1016/0197-4580(91)90006-6
Reed, L. A., Grabowski, T. J., Schmidt, M. L., Morris, J. C., Goate, A., Solodkin, A., et al. (1997). Autosomal dominant dementia with widespread neurofibrillary tangles. Ann. Neurol. 42, 564–572. doi: 10.1002/ana.410420406
Reitz, C., Pericak-Vance, M. A., Foroud, T., and Mayeux, R. (2023). A global view of the genetic basis of Alzheimer disease. Nat. Rev. Neurol. 19, 261–277. doi: 10.1038/s41582-023-00789-z
Ridley, R. M., Baker, H. F., Windle, C. P., and Cummings, R. M. (2006). Very long term studies of the seeding of beta-amyloidosis in primates. J. Neural Transm. (Vienna) 113, 1243–1251. doi: 10.1007/s00702-005-0385-2
Rizzo, S. J. S., Homanics, G., Schaeffer, D. J., Schaeffer, L., Park, J. E., Oluoch, J., et al. (2023). Bridging the rodent to human translational gap: marmosets as model systems for the study of Alzheimer's disease. Alzheimers Dement 9:12417. doi: 10.1002/trc2.12417
Rodriguez-Callejas, J. D., Fuchs, E., and Perez-Cruz, C. (2016). Evidence of tau hyperphosphorylation and dystrophic microglia in the common marmoset. Front. Aging Neurosci. 8:315. doi: 10.3389/fnagi.2016.00315
Rodríguez-Callejas, J. D., Fuchs, E., and Perez-Cruz, C. (2023). Atrophic astrocytes in aged marmosets present tau hyperphosphorylation, RNA oxidation, and DNA fragmentation. Neurobiol. Aging 129, 121–136. doi: 10.1016/j.neurobiolaging.2023.04.010
Rogers Flattery, C. N., Rosen, R. F., Farberg, A. S., Dooyema, J. M., Hof, P. R., Sherwood, C. C., et al. (2020). Quantification of neurons in the hippocampal formation of chimpanzees: comparison to rhesus monkeys and humans. Brain Struct. Funct. 225, 2899–2900. doi: 10.1007/s00429-020-02156-w
Rosen, R. F., Farberg, A. S., Gearing, M., Dooyema, J., Long, P. M., Anderson, D. C., et al. (2008). Tauopathy with paired helical filaments in an aged chimpanzee. J. Comp. Neurol. 509, 259–270. doi: 10.1002/cne.21744
Rosen, R. F., Tomidokoro, Y., Farberg, A. S., Dooyema, J., Ciliax, B., Preuss, T. M., et al. (2016). Comparative pathobiology of β-amyloid and the unique susceptibility of humans to Alzheimer's disease. Neurobiol. Aging 44, 185–196. doi: 10.1016/j.neurobiolaging.2016.04.019
Rosen, R. F., Walker, L. C., and Levine, H. (2011). PIB binding in aged primate brain: enrichment of high-affinity sites in humans with Alzheimer's disease. Neurobiol. Aging 32, 223–234. doi: 10.1016/j.neurobiolaging.2009.02.011
Saito, Y., Ruberu, N. N., Sawabe, M., Arai, T., Tanaka, N., Kakuta, Y., et al. (2004). Staging of argyrophilic grains: an age-associated tauopathy. J. Neuropathol. Exp. Neurol. 63, 911–918. doi: 10.1093/jnen/63.9.911
Schmidt, J. K., Jones, K. M., Van Vleck, T., and Emborg, M. E. (2022). Modeling genetic diseases in nonhuman primates through embryonic and germline modification: considerations and challenges. Sci. Transl. Med. 14:eabf4879. doi: 10.1126/scitranslmed.abf4879
Schmidtke, D., Zimmermann, E., Trouche, S. G., Fontès, P., Verdier, J. M., and Mestre-Francés, N. (2020). Linking cognition to age and amyloid-β burden in the brain of a nonhuman primate (Microcebus murinus). Neurobiol. Aging 94, 207–216. doi: 10.1016/j.neurobiolaging.2020.03.025
Schneider, J. A., Aggarwal, N. T., Barnes, L., Boyle, P., and Bennett, D. A. (2009). The neuropathology of older persons with and without dementia from community versus clinic cohorts. J. Alzheimers Dis. 18, 691–701. doi: 10.3233/JAD-2009-1227
Schneider, A., Biernat, J., von Bergen, M., Mandelkow, E., and Mandelkow, E. M. (1999). Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry 38, 3549–3558. doi: 10.1021/bi981874p
Schultz, C., Dehghani, F., Hubbard, G. B., Thal, D. R., Struckhoff, G., Braak, E., et al. (2000a). Filamentous tau pathology in nerve cells, astrocytes, and oligodendrocytes of aged baboons. J. Neuropathol. Exp. Neurol. 59, 39–52. doi: 10.1093/jnen/59.1.39
Schultz, C., Hubbard, G. B., Rüb, U., Braak, E., and Braak, H. (2000b). Age-related progression of tau pathology in brains of baboons. Neurobiol. Aging 21, 905–912. doi: 10.1016/s0197-4580(00)00176-7
Seita, Y., Morimura, T., Watanabe, N., Iwatani, C., Tsuchiya, H., Nakamura, S., et al. (2020). Generation of transgenic cynomolgus monkeys overexpressing the gene for amyloid-β precursor protein. J. Alzheimers Dis. 75, 45–60. doi: 10.3233/JAD-191081
Selkoe, D. J., Bell, D. S., Podlisny, M. B., Price, D. L., and Cork, L. C. (1987). Conservation of brain amyloid proteins in aged mammals and humans with Alzheimer's disease. Science 235, 873–877. doi: 10.1126/science.3544219
Sengupta, A., Kabat, J., Novak, M., Wu, Q., Grundke-Iqbal, I., and Iqbal, K. (1998). Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. Arch. Biochem. Biophys. 357, 299–309. doi: 10.1006/abbi.1998.0813
Shah, P., Lal, N., Leung, E., Traul, D. E., Gonzalo-Ruiz, A., and Geula, C. (2010). Neuronal and axonal loss are selectively linked to fibrillar amyloid-{beta} within plaques of the aged primate cerebral cortex. Am. J. Pathol. 177, 325–333. doi: 10.2353/ajpath.2010.090937
Sharma, G., Huo, A., Kimura, T., Shiozawa, S., Kobayashi, R., Sahara, N., et al. (2019). Tau isoform expression and phosphorylation in marmoset brains. J. Biol. Chem. 294, 11433–11444. doi: 10.1074/jbc.RA119.008415
Siuda, J., Fujioka, S., and Wszolek, Z. K. (2014). Parkinsonian syndrome in familial frontotemporal dementia. Parkinsonism Relat. Disord. 20, 957–964. doi: 10.1016/j.parkreldis.2014.06.004
Spina, S., Brown, J. A., Deng, J., Gardner, R. C., Nana, A. L., Hwang, J. L., et al. (2019). Neuropathological correlates of structural and functional imaging biomarkers in 4-repeat tauopathies. Brain 142, 2068–2081. doi: 10.1093/brain/awz122
Sridharan, A., Willette, A. A., Bendlin, B. B., Alexander, A. L., Coe, C. L., Voytko, M. L., et al. (2012). Brain volumetric and microstructural correlates of executive and motor performance in aged rhesus monkeys. Front. Aging Neurosci. 4:31. doi: 10.3389/fnagi.2012.00031
Stefanoska, K., Volkerling, A., Bertz, J., Poljak, A., Ke, Y. D., Ittner, L. M., et al. (2018). An N-terminal motif unique to primate tau enables differential protein-protein interactions. J. Biol. Chem. 293, 3710–3719. doi: 10.1074/jbc.RA118.001784
Steuerwald, G. M., Baumann, T. P., Taylor, K. I., Mittag, M., Adams, H., Tolnay, M., et al. (2007). Clinical characteristics of dementia associated with argyrophilic grain disease. Dement. Geriatr. Cogn. Disord. 24, 229–234. doi: 10.1159/000107085
Stoothoff, W. H., and Johnson, G. V. (2005). Tau phosphorylation: physiological and pathological consequences. Biochim. Biophys. Acta 1739, 280–297. doi: 10.1016/j.bbadis.2004.06.017
Strang, K. H., Golde, T. E., and Giasson, B. I. (2019). MAPT mutations, tauopathy, and mechanisms of neurodegeneration. Lab. Investig. 99, 912–928. doi: 10.1038/s41374-019-0197-x
Struble, R. G., Price, D. L., and Cork, L. C. (1985). Senile plaques in cortex of aged normal monkeys. Brain Res. 361, 267–275. doi: 10.1016/0006-8993(85)91298-3
Takuma, H., Arawaka, S., and Mori, H. (2003). Isoforms changes of tau protein during development in various species. Brain Res. Dev. Brain Res. 142, 121–127. doi: 10.1016/s0165-3806(03)00056-7
Thal, D. R., Rüb, U., Orantes, M., and Braak, H. (2002). Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58, 1791–1800. doi: 10.1212/wnl.58.12.1791
Tolnay, M., and Probst, A. (1998). Ballooned neurons expressing alphaB-crystallin as a constant feature of the amygdala in argyrophilic grain disease. Neurosci. Lett. 246, 165–168. doi: 10.1016/s0304-3940(98)00250-x
Trojanowski, J. Q., Schuck, T., Schmidt, M. L., and Lee, V. M. (1989). Distribution of tau proteins in the normal human central and peripheral nervous system. J. Histochem. Cytochem. 37, 209–215. doi: 10.1177/37.2.2492045
Trushina, N. I., Bakota, L., Mulkidjanian, A. Y., and Brandt, R. (2019). The evolution of tau phosphorylation and interactions. Front. Aging Neurosci. 11:256. doi: 10.3389/fnagi.2019.00256
Uchihara, T., Endo, K., Kondo, H., Okabayashi, S., Shimozawa, N., Yasutomi, Y., et al. (2016). Tau pathology in aged cynomolgus monkeys is progressive supranuclear palsy/corticobasal degeneration- but not Alzheimer disease-like -ultrastructural mapping of tau by EDX. Acta Neuropathol. Commun. 4:118. doi: 10.1186/s40478-016-0385-5
Uversky, V. N. (2019). Intrinsically disordered proteins and their "mysterious" (meta)physics. Front. Physiol. 7:10. doi: 10.3389/fphy.2019.00010
Valentino, R. R., Scotton, W. J., Roemer, S. F., Lashley, T., Heckman, M. G., Shoai, M., et al. (2024). MAPT H2 haplotype and risk of pick's disease in the pick's disease international consortium: a genetic association study. Lancet Neurol. 23, 487–499. doi: 10.1016/S1474-4422(24)00083-8
Wade-Martins, R. (2012). Genetics: the MAPT locus-a genetic paradigm in disease susceptibility. Nat. Rev. Neurol. 8, 477–478. doi: 10.1038/nrneurol.2012.169
Wakeman, D. R., Weed, M. R., Perez, S. E., Cline, E. N., Viola, K. L., Wilcox, K. C., et al. (2022). Intrathecal amyloid-beta oligomer administration increases tau phosphorylation in the medial temporal lobe in the African green monkey: a nonhuman primate model of Alzheimer's disease. Neuropathol. Appl. Neurobiol. 48:e12800. doi: 10.1111/nan.12800
Waldö, M. L. (2015). The frontotemporal dementias. Psychiatr. Clin. North Am. 38, 193–209. doi: 10.1016/j.psc.2015.02.001
Walker, M. L. (1995). Menopause in female rhesus monkeys. Am. J. Primatol. 35, 59–71. doi: 10.1002/ajp.1350350106
Walker, L. C., and Jucker, M. (2017). The exceptional vulnerability of humans to Alzheimer's disease. Trends Mol. Med. 23, 534–545. doi: 10.1016/j.molmed.2017.04.001
Walker, L. C., Kitt, C. A., Schwam, E., Buckwald, B., Garcia, F., Sepinwall, J., et al. (1987). Senile plaques in aged squirrel monkeys. Neurobiol. Aging 8, 291–296. doi: 10.1016/0197-4580(87)90067-4
Walker, K. K., Walker, C. S., Goodall, J., and Pusey, A. E. (2018). Maturation is prolonged and variable in female chimpanzees. J. Hum. Evol. 114, 131–140. doi: 10.1016/j.jhevol.2017.10.010
Warren, W. C., Harris, R. A., Haukness, M., Fiddes, I. T., Murali, S. C., Fernandes, J., et al. (2020). Sequence diversity analyses of an improved rhesus macaque genome enhance its biomedical utility. Science 370:6523. doi: 10.1126/science.abc6617
Weingarten, M. D., Lockwood, A. H., Hwo, S., and Kirschner, M. W. (1975). A protein factor essential for microtubule assembly. Proc. Natl. Acad. Sci. USA 72, 1858–1862. doi: 10.1073/pnas.72.5.1858
Wen, Y., Zhou, Y., Jiao, B., and Shen, L. (2021). Genetics of progressive Supranuclear palsy: A review. J. Parkinsons Dis. 11, 93–105. doi: 10.3233/JPD-202302
Wood, B. M., Negrey, J. D., Brown, J. L., Deschner, T., Thompson, M. E., Gunter, S., et al. (2023). Demographic and hormonal evidence for menopause in wild chimpanzees. Science 382:eadd5473. doi: 10.1126/science.add5473
Xia, Y., Prokop, S., and Giasson, B. I. (2021). "Don't Phos over tau": recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer's disease and other tauopathies. Mol. Neurodegener. 16:37. doi: 10.1186/s13024-021-00460-5
Yoshimatsu, S., Seki, F., Okahara, J., Watanabe, H., Sasaguri, H., Haga, Y., et al. (2022). Multimodal analyses of a non-human primate model harboring mutant amyloid precursor protein transgenes driven by the human EF1α promoter. Neurosci. Res. 185, 49–61. doi: 10.1016/j.neures.2022.08.008
Yue, F., Feng, S., Lu, C., Zhang, T., Tao, G., Liu, J., et al. (2021). Synthetic amyloid-β oligomers drive early pathological progression of Alzheimer's disease in nonhuman primates. iScience 24:103207. doi: 10.1016/j.isci.2021.103207
Yue, F., Lu, C., Ai, Y., Chan, P., and Zhang, Z. (2014). Age-associated changes of cerebrospinal fluid amyloid-β and tau in cynomolgus monkeys. Neurobiol. Aging 35, 1656–1659. doi: 10.1016/j.neurobiolaging.2014.01.139
Zhang, J., Chen, B., Lu, J., Wu, Y., Wang, S., Yao, Z., et al. (2019). Brains of rhesus monkeys display aβ deposits and glial pathology while lacking aβ dimers and other Alzheimer's pathologies. Aging Cell 18:e12978. doi: 10.1111/acel.12978
Zhou, F. Q., Jiang, J., Griffith, C. M., Patrylo, P. R., Cai, H., Chu, Y., et al. (2018). Lack of human-like extracellular sortilin neuropathology in transgenic Alzheimer's disease model mice and macaques. Alzheimers Res. Ther. 10:40. doi: 10.1186/s13195-018-0370-2
Keywords: tau, tauopathies, nonhuman primates, Alzheimer’s disease, frontemporal dementia, neurofibrillary tangles, aging, AT8
Citation: Colwell JC and Emborg ME (2025) Tau and tauopathies across primate species: implications for modeling neurodegenerative disorders. Front. Aging Neurosci. 17:1598245. doi: 10.3389/fnagi.2025.1598245
Edited by:
Sylvia Eva Perez, Barrow Neurological Institute (BNI), United StatesReviewed by:
Eric Daniel Hamlett, Medical University of South Carolina, United StatesJessica L. Verpeut, Arizona State University, United States
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*Correspondence: Marina E. Emborg, ZW1ib3JnQHByaW1hdGUud2lzYy5lZHU=