Sec. Pathological Conditions
Volume 9 - 2015 | https://doi.org/10.3389/fnbeh.2015.00268
Dissecting Alzheimer disease in Down syndrome using mouse models
- 1Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK
- 2The LonDownS Consortium, London, UK
Down syndrome (DS) is a common genetic condition caused by the presence of three copies of chromosome 21 (trisomy 21). This greatly increases the risk of Alzheimer disease (AD), but although virtually all people with DS have AD neuropathology by 40 years of age, not all develop dementia. To dissect the genetic contribution of trisomy 21 to DS phenotypes including those relevant to AD, a range of DS mouse models has been generated which are trisomic for chromosome segments syntenic to human chromosome 21. Here, we consider key characteristics of human AD in DS (AD-DS), and our current state of knowledge on related phenotypes in AD and DS mouse models. We go on to review important features needed in future models of AD-DS, to understand this type of dementia and so highlight pathogenic mechanisms relevant to all populations at risk of AD.
Introduction: AD-DS, the Most Common Genetic Form of AD
Down syndrome (DS) is a complex, heterogeneous disorder caused by the presence of an extra copy of human chromosome 21. Trisomy 21 is a common condition, with an incidence of 1 in 750 live births (Parker et al., 2010). Prevalence in many countries is growing due to increasing maternal age, the greatest risk factor for DS (Loane et al., 2013), together with rises in DS life expectancy (Yang et al., 2002; Bittles and Glasson, 2004). In Northern Europe, for example, the number of people aged over 40 years with DS is approximately double what it was in 1990, and in the UK this age group accounts for a third of the estimated 40,000 people with DS (Wu and Morris, 2013).
The clinical presentation of DS varies extensively and includes features present in all individuals, such as cognitive deficits, and those seen in only some people, such as heart defects (Zigman, 2013; Jensen and Bulova, 2014). Alzheimer disease (AD) pathology is found in the brains of virtually all people with DS by 40 years of age (Wisniewski et al., 1985; Mann and Esiri, 1989), and trisomy 21 causes an increased risk of dementia such that approximately one third of the DS population has AD (“AD-DS”) by the age of 60, with an estimated lifetime prevalence of 90% for all people with DS (Prasher and Krishnan, 1993; Holland et al., 1998; Coppus et al., 2006; Margallo-Lana et al., 2007; McCarron et al., 2014). However, while AD-DS is one of the largest contributors to morbidity and mortality in DS (Coppus et al., 2008), not all individuals develop dementia, even by 70 years of age (Krinsky-McHale et al., 2008; Ghezzo et al., 2014). Thus, the DS population has the most common genetic form of early-onset AD, caused by trisomy 21. Studying AD-DS allows investigation of the initial pathogenic events leading to AD and the development of dementia, relevant to both people with DS and to the general population.
One approach to dissecting human disease is through studying mouse models, and a large number of transgenic strains have been generated to understand specific aspects of AD pathology, most of which have human gene mutations that give rise to rare early-onset familial Alzheimer disease (FAD; Braidy et al., 2012; Webster et al., 2014). In the last decade, chromosome engineering techniques have enabled the generation of an array of DS mouse models that will allow us to dissect the genetic contribution of chromosome 21 (Hsa21), or regions of the mouse genome syntenic to Hsa21, to DS phenotypes. These models recapitulate a wide range of DS features, including neurobiological, behavioral and aging-related aspects (Zhang et al., 2012b; Ruparelia et al., 2013). Thus, in the study of AD-DS, mouse models of DS offer an increasingly important approach to understanding pathogenic mechanisms, so informing us about pathways and networks relevant to all populations at risk of dementia.
Here, we present an overview of clinical features of AD-DS, compared to other genetic forms of AD, to highlight human phenotypes that may be assessed in mechanistic studies of mouse models. We then give examples of data from DS mouse models compared to transgenic mice modeling aspects of AD pathology, to illustrate informative findings from both types of model. We also offer examples of potentially helpful data for investigating AD-DS from the outcomes of overexpressing single genes from Hsa21. Finally, we consider the important features for mouse models to enhance our understanding of AD-DS, and therefore the pathogenetic mechanisms relevant to all AD. For brevity, citations may not necessarily be the original papers, but useful reviews or later references.
Genetic Forms of AD, Including AD-DS
The APP gene lies on Hsa21 and encodes the amyloid precursor protein that is at the heart of the amyloid cascade hypothesis of Alzheimer disease (Glenner and Wong, 1984; Hardy and Higgins, 1992; Hardy and Selkoe, 2002). This hypothesis was generated partly from the observation that extracellular plaques in brains of people with AD are composed of Aβ peptides that are products of APP metabolism. The hypothesis suggests that abnormal APP metabolism initiates AD pathogenesis by triggering a set of events that result in Aβ aggregation, particularly of the Aβ42 peptide, in these extracellular plaques. This leads to the formation of intracellular neurofibrillary tangles, primarily composed of the protein tau, and eventually loss of synapses and neurons. The relationship between the histopathological features of AD and dementia is not yet clear (Castellani and Perry, 2014).
The amyloid cascade hypothesis is currently the most widely-accepted paradigm guiding investigations of AD pathogenesis, and is supported at least in part by the rare cases of FAD caused by different mutations in APP, and in the presenilin genes PSEN1 and PSEN2 that affect APP processing. APP mutations may, for example, result in an increase in total Aβ production, or a relative increase in Aβ species associated with pathogenicity (Ryan and Rossor, 2010).
Importantly for understanding AD-DS, the link between APP and AD also extends to gene dose: in rare forms of FAD, duplication of the wildtype APP locus alone (“Dup-APP”) is sufficient to cause highly penetrant early-onset AD (Rovelet-Lecrux et al., 2006; Sleegers et al., 2006). Dup-APP cases demonstrate that the three doses of APP arising from trisomy 21 are likely to be causative for AD-DS. Conversely, although very rare, partial trisomy 21 excluding APP (i.e., with two “doses” of APP) does not appear to lead to AD (Prasher et al., 1998; Korbel et al., 2009).
While people with DS and Dup-APP are at high risk of dementia, presumably in both cases because of APP triplication, there are some intriguing differences in their AD-related clinical features (Wiseman et al., 2015). Examining the effects of different APP genotypes may therefore provide insights into the modulation of APP pathogenesis. Table 1 shows key examples of phenotypes in AD-DS and how these compare with Dup-APP, FAD due to other APP mutations (primarily point mutations) and late-onset sporadic AD (SAD). Mutations in PSEN1 and PSEN2, which do not map to Hsa21, are not included.
However, a difficulty in analysing phenotypes is the considerable heterogeneity in clinical presentation within each APP genotype, even within families with the same mutation. For example, there is a wide variety of non-cognitive symptoms and behavioral changes across all four AD genotypes, including personality changes (Nelson et al., 2001; Ball et al., 2008), hallucinations (Sleegers et al., 2006; Basun et al., 2008; Guyant-Marechal et al., 2008), paranoia (Sleegers et al., 2006; Pilotto et al., 2013), and delusions (Burns et al., 1990), some of which are associated with cognitive decline (Adams and Oliver, 2010). Another important issue in diagnosing AD in AD-DS is that dementia is an additional cognitive deficit acquired on top of the baseline cognitive impairment found in people with DS: distinguishing between cognitive deficits due to intellectual disability, and decline at early stages of AD, is therefore an important challenge. However, diagnosis of dementia by experienced clinicians has been shown to be accurate in DS, and even more reliable than recent operational dementia criteria (Sheehan et al., 2015). Further, a few clinical features stand out in AD-DS—a striking example, albeit one of unknown relevance to AD, is seizure susceptibility in adulthood, which appears heightened by APP duplication, as both AD-DS (84%) and Dup-APP (57%) have significantly higher rates of seizures than SAD (10–20%). This may indicate specific pathways that are progressively disrupted by APP duplication, resulting in damaging electrical activity in the brain.
Dup-APP and FAD caused by APP mutations are relatively rare, and much information about these conditions remains to be gathered, for example, on synaptic dysfunction, oxidative stress and neuroinflammation. In contrast, AD-DS arises in a population with a well-defined genetic basis and a sizeable prevalence, which means it is of great value for investigating AD pathogenesis for everyone at risk of dementia.
Modeling DS, Including AD-DS, in Mice
Human chromosome 21 has synteny with the mouse genome, such that its ortholog genes are found in three blocks with conserved order and gene orientation on mouse chromosomes 10 (Mmu10), Mmu16, and Mmu17 (Hattori et al., 2000; Dierssen et al., 2009); the mouse App gene lies on Mmu16 (Figure 1). Mice with precisely-defined trisomies (or monosomies) have been generated, now usually by chromosome engineering (Brault et al., 2006; Tybulewicz and Fisher, 2006), to provide a set of models that are segmentally trisomic for regions orthologous to Hsa21 (Davisson et al., 1993; Sago et al., 1998; Olson et al., 2004; Li et al., 2007; Herault et al., 2009; Pereira et al., 2009; Yu et al., 2010a; Liu et al., 2011, 2014; Brault et al., 2015).
Figure 1. Human chromosome 21 (Hsa21), orthologous mouse chromosomes (Mmu), and key mouse models of Down syndrome. Diagram representing Hsa21 and its alignment with syntenic regions on Mmus 16, 17, and 10. The orange circle represents the human centromere and mouse models are color-coded and aligned according to the chromosomal segment for which they are trisomic. Numbers in brackets represent the number of protein-coding Hsa21 orthologous genes within each region or mouse model, according to Ensembl release 79 and the breakpoints published in papers referenced here. The Tc1 mouse is the only model which carries Hsa21, though genomic rearrangements and deletions (indicated by breaks in the chromosome) mean the mouse is functionally trisomic for only ~75% of Hsa21 genes (Gribble et al., 2013). All other mouse models carry duplications of mouse orthologues. The Dp1(16)Yey;Dp1(17)Yey;Dp1(10)Yey (or Ts1Yey;Ts3Yey;Ts2Yey) mouse was generated by crossing together three partial trisomy models (Yu et al., 2010a) and spans the entirety of the Hsa21-syntenic regions. The Ts65Dn mouse (Davisson et al., 1993) contains a freely segregating segment of Mmu16, however it is also trisomic for 43 extra protein-coding genes on the centromeric section of Mmu17 that are not relevant to DS (indicated by an asterisk (*) and accompanying text box; Duchon et al., 2011; Reinholdt et al., 2011). The Ts1Cje mouse (Sago et al., 1998) also contains a monosomy of eight protein-coding genes on Mmu12, irrelevant to the DS phenotype (indicated by “#” and accompanying text box. Gene numbers are based on Ensembl release 79, compared to the original seven monosomic genes detailed in Duchon et al., 2011). Other mice are Ts1Rhr or Dp1(16)Rhr mice (Olson et al., 2004); Ts1Yah mice (Pereira et al., 2009); Ts3Yah (previously published as Ts2Yah; Brault et al., 2015); and Ts4Yah mice (previously published as Ts3Yah mice; Herault et al., 2009). Other useful examples of mouse models include the Ts43H model (not shown) which is partially trisomic for Mmu17 including some genes with ortholog on Hsa21 (Vacík et al., 2005). The scale is in megabase pairs (Mb).
Generating many models with different partial trisomies creates a mapping panel in which individual phenotypes may be assessed in several strains, and so assigned to specific trisomic chromosomal region(s). As all DS phenotypes presumably arise from abnormal gene dosage, candidate genes that when present in three copies give rise to all or part of the phenotype, can be chosen from the trisomic critical region. Individual candidate genes can then be studied, for example, in overexpression or knockout models, to assess the effects of different copy numbers of the gene. Figure 1 is an overview of DS mouse models and the chromosomal segments for which they are trisomic. Table 2 details the gene content for each DS mouse model shown, including protein-coding and non-protein-coding genes relevant to human trisomy 21.
Table 2. Trisomic region and triplicated gene content in Down syndrome mouse models shown in Figure 1 compared with Hsa21 (Ensembl release 79).
The most complete mouse model to date, Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+, is trisomic for all Hsa21 syntenic regions and was generated by crossing three DS mouse models, each carrying duplications of the respective Hsa21 orthologous regions on Mmu10, Mmu16 and Mmu17 (Li et al., 2007; Yu et al., 2010a,b; Figure 1). However, the vast majority of studies relating to AD-DS have been performed on the Ts65Dn mouse, as this has been an extremely important “standard model” of DS for many years, prior to the development of newer strains by chromosome engineering (Davisson et al., 1993; Reeves et al., 1995; Table 2). The Ts65Dn mouse carries a Robertsonian translocation resulting in trisomy of ~42% of the protein-coding genes orthologous to Hsa21, but it also has 79 additional genes (including long non-coding sequences) from Mmu17 that are outside the Hsa21 region of synteny, and these need to be taken into account when analysing phenotypes (Duchon et al., 2011; Reinholdt et al., 2011). These extra triplicated genes that do not relate to DS happen to include non-Hsa21 genes, such as SYNJ2 and TIAM2 that have Hsa21/Mmu16 paralogues (SYNJ1, TIAM1), which may complicate phenotype-genotype correlations (Duchon et al., 2011). Other triplicated genes in Ts65Dn irrelevant to DS include several genes encoding dynein light chains that may influence endosomal trafficking, and so potentially affect neuronal phenotypes (Hartley et al., 2015).
A different type of mouse model of DS is the “humanized” transchromosomic “Tc1” mouse that carries a freely-segregating Hsa21 (O'Doherty et al., 2005), which is functionally trisomic for ~75% of Hsa21 protein-coding genes (Gribble et al., 2013). However, this extra chromosome is rearranged, and lost stochastically at different rates in different mouse tissues—thus, Tc1 mice are mosaic for the human chromosome. With respect to AD research, the APP gene is not functionally trisomic in Tc1 mice because of a rearrangement that has occurred by chance, so this animal expresses just the two endogenous copies of mouse App (Sheppard et al., 2012).
While many DS mouse models have been published, there is no single complete model, and the usefulness of these strains lies in their comparative and complementary use in studying genotype-phenotype relationships, including AD-related phenotypes (Table 3). These studies enable us to map critical dosage-sensitive genes because each locus is likely expressed at trisomic levels, mimicking human DS transcription. We can also study the interactions of Hsa21 dosage-sensitive genes with the rest of the genome (Hsa21 and non-Hsa21), as well as effects exerted by aneuploidy per se.
Table 3. Examples of AD phenotypes studied in DS mouse models, and related findings in APP transgenic strains described in Table 4.
Modeling Amyloid Deposition in Mice
In contrast to the segmental duplication of tens of endogenous wildtype genes in DS mouse strains, AD models are primarily transgenic lines that overexpress one or more of the human mutant genes that cause FAD. These transgenes usually insert at random sites in the genome and may be driven by artificial promoters (see examples in Table 4), which vary in terms of their spatial and temporal expression patterns, and result in expression at often 5–10 fold compared to endogenous mouse orthologue (Balducci and Forloni, 2011; Hall and Roberson, 2012). Overexpressing wildtype human APP or mouse App does not result in amyloid deposition (Elder et al., 2010); hence the need to use known AD-causative mutant sequences in transgenic mice.
Table 4. Human APP overexpressing transgenic mice referred to in this review (information obtained from Alzforum.org).
In general, while mutant APP transgenic mice develop robust amyloid deposition, synaptotoxic features and memory impairments, none of them reproduces tau-containing neurofibrillary tangles, the hallmark pathology of AD which most closely correlates with dementia (Hall and Roberson, 2012). The combined overexpression of mutant APP and mutant human tau is required to reproduce both amyloid and tau pathology, although these tau mutations in humans do not alone cause AD but another form of neurodegeneration, frontotemporal dementia. Mutant APP transgenics may be best considered models of APP/Aβ pathology (amyloid deposition) rather than full AD.
Studying AD-DS Phenotypes in Mice
In Table 3, we summarize examples of findings that may be informative for AD-DS from different DS (mainly Ts65Dn) mice and examples of AD models (Table 4). With respect to AD, a wide range of mutant APP transgenic strains are available in the literature, so we have chosen a few well-known examples [APP22, APP23, APP (V717I), PDAPP, Tg2576, TgCRND8] to illustrate some potential phenotypes of interest. We note that the expression of wildtype mouse APP, and wildtype or mutant human APP protein in these different models can influence amyloid pathology (Kokjohn and Roher, 2009). For example, because of amino acid differences between the two species, mouse APP may be processed with little BACE1 cleavage and so may yield three times less Aβ than wildtype human APP (De Strooper et al., 1995). In addition, the genetic background of AD mouse strains affects a range of APP/Aβ phenotypes, including plaque deposition, APP metabolism, survival, and seizure rates (Carlson et al., 1997; Lehman et al., 2003; Krezowski et al., 2004; Lassalle et al., 2008; Rustay et al., 2010; Jackson et al., 2015). Similarly, phenotypes observed in DS mice may be influenced by genetic background (O'Doherty et al., 2005; Galante et al., 2009; Costa et al., 2010; Deitz and Roper, 2011; Haydar and Reeves, 2012). We consider only APP transgenic models of AD, as the other genes used in such models (PSEN1, PSEN2, and MAPT) are not encoded on Hsa21, and therefore are not directly relevant to AD-DS.
In studying mouse phenotypes to understand AD-DS, we are presented with two key issues. Firstly, we need to test longitudinally DS models to look for changes in older mice that are not apparent early on, and so may indicate aging or neurodegenerative processes rather than neurodevelopmental deficits. Secondly, we need to separate normal aging processes in DS from those connected specifically to AD-DS. The thoughtful use of the increasing range of different mouse models is enabling us to dissect these issues to further our understanding of AD-DS.
A study that has addressed both (1) neurodegenerative vs. neurodevelopmental and (2) normal aging vs. AD phenotypes has been performed in the Ts65Dn mouse. This study concerned the neurodegenerative phenotype loss of basal forebrain cholinergic neurons (BFCNs), and was carried out through an experimental design involving optimal crossing of different mouse models and assessment of the genetically-distinct progeny (Salehi et al., 2006). Firstly, Salehi and colleagues quantified the known loss of BFCNs in Ts65Dn mice, and showed this loss to be progressive, thus an aging or an AD-related phenotype in this DS mouse model. The authors then compared BFCN loss in Ts65Dn and Ts1Cje DS mouse models (Figure 1), and were able to map a dosage-sensitive critical region that had to contain a candidate gene for this phenotype: Ts65Dn mice lose BFCNs but Ts1Cje mice turned out to have no loss compared to wildtype mice. Therefore, the dosage-sensitive gene(s), that when present in three copies is responsible for BFCN loss, must map within the region of trisomy present in Ts65Dn but not in Ts1Cje. A key candidate in this region was the App gene. By crossing Ts65Dn mice to heterozygous App knockout mice, the authors generated cohorts of progeny that carried the trisomic region with either two or three copies of wildtype App. Assessing BFCN loss in these cohorts led to the conclusion that the phenotype arises mainly from having three copies of App and, further, that it is associated with impairments in nerve growth factor retrograde transport, linked to early endosomes, which are enlarged (Salehi et al., 2006).
Given the role of APP triplication in this phenotype, there is likely a strong link to AD and AD-DS. In people with early AD pathology or mild cognitive impairment, neurofibrillary pathology has been detected in BFCNs (Mesulam et al., 2004; Grudzien et al., 2007), while their loss has been observed in patients with SAD (and other neurodegenerative disorders; Zarow et al., 2003). Interestingly, enlarged early endosomes have been detected in cortical tissues from cognitively intact individuals with mild AD pathology, and in young individuals with DS (under 12 years old), suggesting that endosome enlargement is an early feature in AD pathogenesis (Cataldo et al., 2000).
DS Models in the Study of Candidate Genes Influencing AD
As illustrated in Table 1, while people with DS have three copies of APP and develop early AD neuropathology, their clinical presentation is variable, suggesting that other genetic and environmental factors influence pathogenesis. In addition to APP, many genes on Hsa21 have been studied in the context of neurodegeneration and/or AD, and it is conceivable that a three-copy dose of any of these genes could contribute to disease and dysfunction.
Single gene overexpressing transgenics do not model DS, or AD-DS, but may provide some insights if carefully considered. For example, seizures and neuronal network abnormalities remain challenging areas to investigate but important phenotypes to be explored in DS, AD-DS, and APP overexpression models of AD (i.e., which are single gene transgenic models). In SAD, seizures have been associated with early cognitive decline (Vossel et al., 2013), while the incidence of seizures in AD-DS is high and is associated with increased risk of dementia (for example, McCarron et al., 2014). To date, seizure phenotypes and epileptiform activity have been characterized across numerous APP transgenic mice (Born, 2015), but it is unclear whether these phenotypes are primarily driven by amyloid overproduction (Mucke and Selkoe, 2012) or are an effect of unphysiological APP overexpression during development (Born et al., 2014). Antiepileptic drugs, such as levetiracetam, which improve seizures in DS (Sangani et al., 2010) and in AD (Cumbo and Ligori, 2010), also ameliorate synaptic and memory dysfunctions in APP transgenic mice by suppressing neuronal network dysfunction (Sanchez et al., 2012; Devi and Ohno, 2013).
So, while single gene transgenic models do not model human trisomy 21 or AD because they usually express the gene by many-fold, from ectopic promoters, they offer insights into some of the functional consequences of overexpression, albeit at non-trisomic levels. Table 5 presents a list of Hsa21 gene candidates, in chromosomal order, that have been investigated for overexpression-related phenotypes linked with AD across different mouse, fruitfly, and cellular models. We also compare, where data are available, how related changes in these genes have been explored in humans with AD and/or DS. Making optimal use of mouse genetics, some of the single-gene-overexpressing mouse transgenics have been crossed with AD models, to look for changes in phenotypes that may be informative. For example, crossing an S100β overexpression model with the Tg2576 APP transgenic mouse generates double mutant progeny with exacerbated cerebral amyloidosis and reactive gliosis. This suggests that increased expression of S100β could contribute to AD pathogenesis possibly by promoting amyloidogenic APP processing (Mori et al., 2010).
Table 5. Single gene overexpression models from Hsa21, with relevance to AD phenotypes. Genes are listed in order from centromere to Hsa21q telomere.
Other key Hsa21 gene candidates DYRK1A and RCAN1 have been linked to AD pathogenesis through their effects on tau. The toxic neurofibrillary tangles (NFTs) that accumulate in AD are formed of hyperphosphorylated tau protein. Overexpression of DYRK1A in transgenic mice resulted in tau hyperphosphorylation (Ryoo et al., 2007, 2008), and DYRK1A has been shown to co-localize with NFTs more frequently in AD-DS brain compared to SAD (Wegiel et al., 2008). Similarly, overexpression of RCAN1 in a mouse model resulted in abnormal tau hyperphosphorylation (Wegiel et al., 2011). This suggests that the increased expression of DYRK1A and RCAN1 in DS could promote the formation of NFTs, a hallmark feature of AD pathology.
Triplication of Hsa21 genes in DS does not necessarily lead to a 1.5-fold increase (compared to euploid individuals) in their RNA or protein expression. For example, a study in DS fetal cortical tissue revealed multiple Hsa21 proteins in fact expressed at similar or lower levels than in disomic controls (Cheon et al., 2003a,b,c,d). Assessments at transcriptomic and proteomic levels, together with meta-analysis across these studies, provide useful resources for understanding patterns of alteration in gene expression (for example, see Vilardell et al., 2011). As a few of the studies in Table 5 have demonstrated, it is important to verify the effect of trisomy on candidate gene expression, in relevant tissues and contexts, before further characterization of any potential downstream effects of trisomy.
Prospects for Research
Individuals with DS manifest the most common genetic form of AD, and this undoubtedly largely arises from expressing three copies of APP (Ness et al., 2012; Hartley et al., 2015). Therefore, studying and modeling this population will assist in understanding the contribution of APP to AD pathogenesis, and evaluating the amyloid cascade hypothesis. However, the variation in clinical presentation of AD-DS shows that many other genetic and environmental factors contribute, almost certainly including protective factors. The thoughtful use of models will thus provide insight into these factors.
To study mouse models of AD-DS, it is critical to dissect neurodevelopmental from neurodegenerative effects (Bothwell and Giniger, 2000; Contestabile et al., 2010). To be of interest for AD-DS, such phenotypes should differ from normal aging in the mouse strain of interest, although this can be difficult to determine, particularly as DS has been characterized as a syndrome of accelerated aging in both clinical (Lott, 2012; Zigman, 2013) and epigenetic terms (Horvath et al., 2015), and because aging remains the clearest non-genetic risk factor for all forms of AD (Fratiglioni, 1996; Bush and Beail, 2004). The longitudinal study of cognitive decline in DS mice poses similar challenges to those in people with DS, and tests need to distinguish between dysfunction due to dementia, as opposed to aging or baseline learning deficits. For example, variations of a learning procedure involving incremental repeated acquisition tasks suggest that declining performances by Ts65Dn mice with age may be due to motor impairments and/or decreased motivation, rather than neurodegenerative-related effects (Sanders et al., 2009). To improve behavioral testing in mouse models of AD-DS, a potential avenue to explore capitalizes on the association of dementia with deficits in episodic memory. The development of tests based on, for example, visuo-spatial data, should therefore highlight age-dependent, dementia-related deficits in mouse models, because they rely on the encoding and binding of information spontaneously, and do not challenge other cognitive domains (Iordanova et al., 2009).
As well as the hypothesis-driven study of AD-DS phenotypes, one of the greatest strengths of working with mouse models is our ability to undertake unbiased hypothesis-generating research, by mapping phenotypes to genomic critical regions using the range of strains now available. These include chromosome-engineered panels of partially trisomic mice (Figure 1) as well as single gene knockout animals, such as the App+∕− heterozygous mice, which may be crossed to partially trisomic strains, to generate progeny with altered single gene copy numbers on different trisomic region backgrounds. The cohorts of progeny from these crosses provide ideal groups for testing the contributions of single Hsa21 genes to AD-DS.
Mouse genome engineering continues to offer new models and approaches for teasing apart AD-DS relevant phenotypes, and new strains are being published regularly to help refine experimental strategies. For example, the recent genomically humanized NLF mouse (Saito et al., 2014), which has human amino acid residues at key sites within APP that affect its processing, may yield new insights into the biology of both AD and AD-DS, partly through expressing mutant APP at physiological levels. The strategic breeding of new APP models with DS segmental trisomies will contribute to determining which phenotypes are downstream of an amyloid cascade. Furthermore, independent study of partial trisomies without three copies of App may help tease out effects of other factors, for example oxidative stress, cholesterol metabolism or immune system dysfunction, in the development of dementia (Wiseman et al., 2015).
DS mouse models also give us the flexibility to investigate the effects of potentially dosage-sensitive non-coding regions. For example, microRNAs (miRs)—short (20–23 nucleotide) RNAs that downregulate the transcription of target genes—have increasingly been investigated in AD pathogenesis due to their differential regulation in molecular pathways associated with AD (Veerappan et al., 2013). Hsa21 encodes 29 miRs (MirBase release 21, Griffiths-Jones, 2004), and their potential overexpression in trisomy may contribute to genetic dysregulation relevant to AD-DS. Overexpression of the Hsa21-encoded miR-155 in DS has been reported to increase Aβ production via the downregulation of sorting nexin 27, a membrane-trafficking component found in early endosomes, that modulates γ-secretase activity (Wang et al., 2013, 2014).
Hsa21 also encodes genes involved in post-translational histone modification, including DYRK1A, ETS2, HMGN1, BRWD1, and RUNX1 (Dekker et al., 2014), which may be investigated for their potential roles leading to the aberrant histone modifications observed in AD (Zhang et al., 2012a; Narayan et al., 2015). Histone methylation (specifically H3K4me3) has been shown to correlate highly with genome-wide domains of dysregulated gene expression in DS, which are highly conserved between humans and Ts65Dn mice (Letourneau et al., 2014). DS mouse models therefore model epigenetic structures in humans and may be used to study the effects of its dysregulation in AD-DS.
Finally, mouse model research must be undertaken in parallel with other rapid advances in the AD-DS field. The advent of human induced pluripotent stem (iPS) cells (Hunsberger et al., 2015) for DS provides for the first time a trisomic human in vitro model that recapitulates hallmarks of some AD pathology (Shi et al., 2012; Chang et al., 2015; Moore et al., 2015; Murray et al., 2015). The further development of this technology (Hunsberger et al., 2015) will prove valuable to phenotyping and drug target discovery, alongside in vivo research and in vitro primary cultures from DS mice. An increasing call is being made for partnerships to build up large cohorts of, and biobanks from, people with DS for the systematic longitudinal study of AD-DS progression (Hartley et al., 2015). In-depth phenotypic studies across development with infants and adults with DS are already underway (Wiseman et al., 2015). These will allow greater power to identify biomarkers for the prediction of AD in this large, genetically well-defined population, for example, through plasma (Dekker et al., 2015; Schupf et al., 2015), cerebrospinal fluid (Portelius et al., 2014a,b), and neuroimaging studies (Beacher et al., 2009; Landt et al., 2011; Powell et al., 2014; Sabbagh et al., 2015). Biomarker studies are also being performed in AD models, including at very early phases of Aβ deposition (Maia et al., 2015). Extending these studies to mouse models of DS and AD-DS will contribute to elucidating the genotype-phenotype relationships that ultimately lead to dementia.
Conflict of Interest Statement
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.
We would like to thank members of the London Down Syndrome Consortium (LonDownS) for their constructive feedback to this review, in particular Annette Karmiloff-Smith, Carla Startin, Andre Strydom, Victor Tybulewicz, Frances Wiseman, as well as Veronique Brault, Mark Good, Eva Lana-Elola and Sheona Watson-Scales for their generous comments and advice. XYC is funded by the Brain Research Trust, JT is funded by the Alzheimer's Society, LP is funded by Alzheimer's Research UK, EF is funded by the Wellcome Trust.
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Keywords: Alzheimer disease, APP, Down syndrome, mouse models, trisomy 21
Citation: Choong XY, Tosh JL, Pulford LJ and Fisher EMC (2015) Dissecting Alzheimer disease in Down syndrome using mouse models. Front. Behav. Neurosci. 9:268. doi: 10.3389/fnbeh.2015.00268
Received: 22 May 2015; Accepted: 21 September 2015;
Published: 13 October 2015.
Edited by:Roger H. Reeves, Johns Hopkins University, USA
Reviewed by:Sebastian Herbert Scharf, F. Hoffmann-La Roche Ltd, Switzerland
Yann Herault, Centre National de la Recherche Scientifique, France
Alexander M. Kleschevnikov, University of California, San Diego, USA
Copyright © 2015 Choong, Tosh, Pulford and Fisher. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Elizabeth M. C. Fisher, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK, firstname.lastname@example.org