Abstract
Alzheimer’s disease (AD) is a complex, multifactorial disorder, influenced by a multitude of variables ranging from genetic factors, age, and head injuries to vascular diseases, infections, and various other environmental and demographic determinants. Among the environmental factors, the role of the microbiome in the genesis of neurodegenerative disorders (NDs) is gaining increased recognition. This paradigm shift is substantiated by an extensive body of scientific literature, which underscores the significant contributions of microorganisms, encompassing viruses and gut-derived bacteria, to the pathogenesis of AD. The mechanism by which microbial infection exerts its influence on AD hinges primarily on inflammation. Neuroinflammation, activated in response to microbial infections, acts as a defense mechanism for the brain but can inadvertently lead to unexpected neuropathological perturbations, ultimately contributing to NDs. Given the ongoing uncertainty surrounding the genetic factors underpinning ND, comprehensive investigations into environmental factors, particularly the microbiome and viral agents, are imperative. Recent advances in neuroscientific research have unveiled the pivotal role of non-coding RNAs (ncRNAs) in orchestrating various pathways integral to neurodegenerative pathologies. While the upstream regulators governing the pathological manifestations of microorganisms remain elusive, an in-depth exploration of the nuanced role of ncRNAs holds promise for the development of prospective therapeutic interventions. This review aims to elucidate the pivotal role of ncRNAs as master modulators in the realm of neurodegenerative conditions, with a specific focus on Alzheimer’s disease.
1 Introduction
Alzheimer’s disease (AD) represents a devastating and globally prevalent neurodegenerative disorder, characterized as the most common form of dementia. Recent statistics from the Centers for Disease Control and Prevention (CDC) reveal that nearly 6 million individuals in the United States alone are afflicted by AD (). The etiology of AD remains enigmatic due to its intricate interplay with various organ systems and multicellular interactions, often initiated by microbial infections. Infections targeting the central nervous system (CNS) present a grave and frequently fatal health concern, with survivors often grappling with enduring neurological impairments (). To unravel the intricate mechanisms governing the impact of microbes on CNS function, it becomes paramount to delve into the regulatory role of non-coding RNAs (ncRNAs) as their significance in numerous disease states has garnered increasing recognition. Notably, the precise mechanisms underlying the contribution of human viral infections or perturbations in the host microbiome to the onset of AD remain elusive, potentially involving intricate ncRNA-mediated processes. Perturbations in ncRNAs can exert profound effects on disease states, thus emphasizing the critical importance of comprehending these molecules and the factors influencing them. Such insights hold promise for manipulating the mechanisms that influence brain function, offering prospects for ameliorating or delaying the progression of neurodegenerative pathology ().
2 Clinical and cellular mechanisms in Alzheimer’s disease
Alzheimer’s disease (AD) is characterized by a spectrum of clinical and pathological features, encompassing synaptic loss, neuronal damage, alterations in plasticity, and the aggregation of senile plaques composed of Aβ and tau proteins, ultimately culminating in progressive neural system dysfunction over time (Valenza and Scuderi, 2022). Predominantly, AD patients grapple with memory loss as the cardinal clinical manifestation (). Additionally, AD patients often exhibit mild language impairments and judgment deficits (). Neuropsychiatric symptoms, including behavioral changes, can also be observed in individuals with AD (). The pathophysiological landscape of AD is multifaceted, underpinned by various hypotheses, including the roles of (a) amyloid-β, (b) Tau pathology leading to neurofibrillary tangles, (c) mitochondrial dysfunction, and reactive oxygen species (ROS) generation, among others (). Amyloidosis, a hallmark feature of Alzheimer’s disease (AD), is characterized by the aggregation of amyloid peptides within cells and tissues, giving rise to disruptive plaques. Aβ peptides can further self-aggregate through complex mechanisms, leading to organ damage. A central player in the amyloidogenic cascade is the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) enzyme. It cleaves the amyloid precursor protein (APP) at the β site, leading to the production of amyloid β-1 (). This event is pivotal in AD as the excessive accumulation of amyloid plaques underlies disease pathogenesis. Intriguingly, alterations in BACE1 expression have been linked to neuropathological conditions, suggesting a tightly regulated process governed by non-coding RNAs (ncRNAs; Zhou et al., 2021; ; ).
Neural cells have been reported to produce higher quantities of Aβ compared to other cell types. Aβ is a crucial component involved in intracellular signaling cascades and various physiological functions within the central nervous system (CNS; ). Another key aspect of AD is tau pathology. As a microtubule-associated protein, tau contributes to microtubule assembly and related protein interactions. Aberrant tau phosphorylation disrupts microtubule integrity, resulting in synaptic dysfunction and increased neurite branching (). Tau oligomers have been implicated as initiators of deficits in axonal transport, resulting in neural damage and eventual cell death. The mitochondrial damage hypothesis suggests that Aβ accumulation within brain mitochondria can alter their structure and function. These changes are associated with increased Aβ levels, leading to energy generation imbalances and respiratory deficits (). Aβ oligomer buildup within the mitochondria can also stimulate bidirectional reactive oxygen species (ROS) production, which can be toxic to neural cells (). Methylation of mitochondrial tRNA, a small non-coding RNA, has been observed in elderly individuals, whether they are healthy or have Alzheimer’s disease (AD). This methylation can potentially impact mitochondrial protein biosynthesis and contribute to mitochondrial dysfunction, which is an early hallmark of neurodegeneration and age-related disorders (). Changes in the expressions of tRNA-related fragments (TRFs) have been noted in the hippocampus of AD patients, and these changes appear to be age- and disease-stage dependent (Wu et al., 2021). Gender differences in brain development have significant implications for the investigation of neuropsychiatric and neurodegenerative disorders, including AD. Brain pathology in female patients with AD, compared to male patients, underscores the role of sex differences in the progression of AD (). Aberrant expressions of corticotropin-releasing factor (CRF) in female patients have been correlated with increased tau phosphorylation, a pathological step in the formation of neurofibrillary tangles seen in AD (). Gender-associated long non-coding RNAs (lncRNAs), such as SLC25A25-AS1, LY86-AS1, and PWRN1, have been identified as highly dysregulated in AD brains although further studies are warranted to elucidate their precise roles in AD pathology (). Observations through brain MRI reveal ventricle enlargement and cerebral cortex shrinkage, indicative of Alzheimer’s pathology. These structural changes impact memory, intelligence, judgment, behavior, and language in Alzheimer’s patients (). Furthermore, disruptions in the blood–brain barrier (BBB) are evident, characterized by altered endothelial cell connections, leading to enhanced fluid transcytosis, pericyte loss, compromised tight junction proteins, and cerebral microhemorrhages (Figure 1; ).
Figure 1
3 Non-coding RNAs
Non-coding RNAs (ncRNAs) constitute a diverse group of RNA molecules that, primarily, do not encode proteins. Their multifaceted roles in cellular processes and pathophysiological conditions have garnered increasing attention in contemporary molecular biology. These ncRNAs participate in gene regulation, epigenetic modifications, and RNA processing, contributing significantly to normal neuronal function (). They can be broadly categorized into two major groups: circular RNAs and linear RNAs, as illustrated in Figure 2. Linear RNAs further branch into housekeeping and regulatory elements (). The housekeeping group encompasses transfer RNA (tRNA), ribosomal RNA (rRNA), small nuclear RNA (snRNA), and small nucleolar RNA (snoRNA). Regulatory elements, based on their lengths, segregate into long ncRNAs (lncRNAs) and short ncRNAs or small ncRNAs (sncRNAs; Zhang et al., 2019). Intergenic and intronic divisions are found within lncRNAs (). Pioneering studies have unveiled that conserved regions within intergenic lncRNAs are significantly enriched in protein-RNA interaction signatures, contrasting non-conserved counterparts such as Malat1, Neat1, and Meg3 (). SncRNAs encompass various subsets such as microRNAs (miRNAs), small-interfering RNAs (siRNAs), and piwi-interacting RNAs (piRNAs), among others (). MiRNAs, highly conserved in evolution, modulate nearly 50% of genes post-transcriptionally, serving as critical regulators in brain development, neuronal processes including apoptosis, proliferation, and differentiation (). SiRNAs are involved in posttranscriptional gene silencing although not exclusively (). PiRNAs contribute to diverse neural events, including genomic heterogeneity, neuronal response to injuries, behavior, and memory formation (; ). Regulatory RNAs exhibit the potential to manipulate cellular processes, and their aberrant expressions can underpin disease etiology in specific cases (). In the context of diagnostics, ncRNAs offer valuable tools for molecular biology due to their relative stability in the bloodstream. For example, NEAT1, an ncRNA, plays a pivotal role in chromatin remodeling and microtubule integrity. The downregulation of NEAT1 may enhance the expression of phosphorylated Tau protein, leading to microtubule dysfunction via the Frizzled Class Receptor 3/CSK3β/p-tau pathway (Zhao et al., 2020). Linc00507, another long intergenic non-protein coding RNA, has been associated with AD pathology through enhanced tau phosphorylation (). The dysregulation of NDM29, BC200, 17A, and 51A ncRNAs has been correlated with AD pathology linked to Aβ accumulation (). Recent scientific endeavors have spotlighted the hypothesis that microorganisms, particularly those of viral and bacterial origin, may significantly contribute to neurodegenerative processes, potentially employing ncRNAs as mediators in the manifestation of brain impairments.
Figure 2
4 Gut microbiome and Alzheimer’s disease
Recent research has shed light on the intricate relationship between the gut microbiome and Alzheimer’s disease (AD) pathology, yet several crucial gaps in understanding remain to be addressed. Human studies, particularly interventional investigations, are needed to draw definitive conclusions regarding the mediating role of non-coding RNAs (ncRNAs) in the initiation and progression of neurodegenerative diseases, including Alzheimer’s, ultimately providing practical avenues for therapeutic interventions ().
Mounting evidence suggests that dysbiosis of gut microbiota can contribute to AD pathogenesis through microbial metabolites, such as Bacteroides fragilis toxins (BFT) and lipopolysaccharide (LPS; ), which actively engage neurotransmitters and ncRNAs in gut–central nervous system (CNS) communication (). BFT, for instance, influences the CNS by modulating the NF-κB pathway and upregulating miRNA-146a expression, potentially inciting neuroinflammation and neurodegeneration (Zhao and Lukiw, 2018a). LPS, on the other hand, can increase the expression of miRNAs-34a and 146a, targeting genes implicated in sporadic AD (). While the precise role of miRNAs in gut–brain communication remains elusive, the potential interplay between microbial metabolites and ncRNAs is evident. For instance, butyrate induces miR-375 expression and regulates tryptophan metabolism, a process associated with AD neuropathogenesis and cognitive dysfunction ().
Exploring the connection between bacterial toxins, gastrointestinal (GI) barrier permeability, and the role of different ncRNAs in facilitating the passage of molecules through the blood–brain barrier (BBB) is essential (; ). The role of BFT in GI barrier disruption has been documented through synaptic E-cadherin cleavage in GI epithelial cells, emphasizing the need to examine bacterial metabolites with neurotoxic potential (Zhao and Lukiw, 2018b). Additionally, the severity of inflammation in sepsis is closely linked to miR-486-5p expression, a diagnostic biomarker of sepsis, which may enhance microglial activity and contribute to persistent inflammation (; Zhang M. et al., 2021; ).
In recent research, specific miRNAs have emerged as critical regulators of innate responses to infections, and symbiotic bacteria have been found to downregulate the expression of miRNA-10a in dendritic cells through interactions with toll-like receptors (TLRs) and ligands (Xue et al., 2011; ; ; Zhao et al., 2021). Another type of non-coding RNA, H19, plays a significant role in pro-inflammatory responses induced by pathogens. It achieves this through modulation of the NF-κB signaling pathway. Moreover, H19 has implications for glucose metabolism and insulin-dependent signaling, potentially linking diabetes and Alzheimer’s disease (; ).
The altered composition of the gut microbiota is a common observation and can significantly impact the progression of Alzheimer’s disease (; ). The complex relationship between the gut microbiota composition and specific miRNA expression in the brain is of particular interest. This bidirectional interaction has implications for anxiety and depression-related behaviors, highlighting the potential role of non-coding RNAs as mediators in the gut–brain axis. Studies suggest that disturbances in the gut microbiota can trigger processes such as apoptosis, ROS generation, and neurodegeneration (). It is worth noting that miRNAs influenced by pathogens may play a role in neuropsychiatric disorders, further supporting the theory of the gut microbiota–ncRNA–brain axis ().
In summary, disturbances in the gut microbiota can lead to fluctuations in ncRNA modulation profiles, ultimately resulting in brain dysfunction (). Table 1 provides a more detailed exploration of gut microbiome derivatives implicated in AD pathology.
Table 1
| Gut-derived products | Beneficial effect on brain functions | Detrimental effect on brain functions |
|---|---|---|
| BFT and BF-LPS | BFT is found to be among the most pro-inflammatory lipoglycans—BFT alters GI tract and BBB structure, integrity, and permeability () | |
| LPS | In gut microbial dysbiosis associated with aging, the increased paracellular permeability of the gut permits LPS to escape into the bloodstream. The BBB becomes more permeable with age, allowing circulating pro-inflammatory LPS to enter the brain tissue—LPS can be used as a biomarker of AD () | |
| SCFAs (e.g., butyrate) | Neurogenesis, microglial maturation, reduction of cognitive impairments | |
| GABA | Neuroprotective effect in neurodegenerative conditions | Reduced GABA levels in the brains of AD patients have been reported () |
| Histamine | Histamine elevates nitric oxide (NO) levels and induces neuroinflammation (Zhang Y. et al., 2021) |
Gut microbiome-derived products in Alzheimer’s disease (AD) pathology.
This table provides a summary of the impact of gut microbiome-derived products on brain functions within the context of Alzheimer’s disease (AD) pathology. These products can have both beneficial and detrimental effects, highlighting the intricate relationship between gut health and brain function in AD.BFT, Bacteroides fragilis toxins; LPS, lipopolysaccharide; SCFA, short-chain fatty acids; GABA, gamma-aminobutyric acid; NO, nitric oxide; AD, Alzheimer’s disease.
4.1 Positive effects of microbiome changes
The human gut microbiome (GM) plays a pivotal role in maintaining overall health and can significantly impact various disease states, as depicted in Figure 3. Notably, certain Lactobacillus strains originating from the GM have a positive impact on human brain health. Extensive research has provided compelling evidence that a metabolite called lactate, produced by the Lactobacillus family, contributes to the upregulation of sirtuin1 deacetylase (Sirt1) through the mediation of Sirt1 antisense (AS) lncRNA. This particular lncRNA engages in competitive interactions with miRNA-34a, ultimately rescuing the Sirt1 mRNA transcript from repression. The intricate mechanism involving lactate-induced neurotrophic factors in the hippocampus, facilitated by the Sirt1-AS lncRNA, indirectly leads to enhanced synaptic plasticity (Wang et al., 2016; ; ; ). This connection underscores the significance of the gut–brain axis in neurodegenerative conditions and opens avenues for therapeutic interventions (Figure 3).
Figure 3
4.2 Negative effects of microbiome changes
There is growing interest in understanding how the GM might impact neurodegenerative disorders such as Alzheimer’s disease (AD), as indicated by , , and . The connection between the GM and AD involves a range of pathological mechanisms, including deposition of amyloid-β, hyperphosphorylation of tau, neuroinflammation, mitochondrial dysfunction, and metabolic alterations (Wang et al., 2016; ; ). Non-coding RNAs (ncRNAs) have emerged as key regulators of the host’s responses to pathogenic microbiota. However, it is crucial to underscore the importance of conducting rigorous investigations to validate the interactions between pathogens and ncRNAs within the context of the brain.
5 Human bacterial infections and Alzheimer’s disease
Bacterial metabolites and components, including substances such as LPS, peptidoglycan (PG), and lipoprotein, possess the ability to influence the expression of host non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), which can lead to the development of pro-inflammatory conditions that indirectly impact neurodegeneration. An example of this is miRNA-1224, which significantly increases following exposure to LPS, thereby contributing to LPS-induced inflammation by regulating tumor necrosis factor-alpha or (TNF-α) through an SP1 binding site, associated with increased levels of miRNA-1224 in AD patients, suggesting a potential link between LPS, a component of Gram-negative bacteria, and the pathogenesis of AD (; ). Furthermore, it is noteworthy that, microbial agents often employ the NF-κB signaling pathway, mediated by miRNA-146a, as a means to promote neurodegeneration.
5.1 Periodontitis, nasal microbiome, and Alzheimer’s disease
Severe periodontitis can have a significant impact on tooth health and increase the risk of various diseases, including AD. Periodontitis can trigger the release of pro-inflammatory cytokines, potentially leading to increased deposition of Aβ in the brain. However, the intricate relationship between periodontitis and Alzheimer’s disease requires further research for a comprehensive understanding. In particular, Porphyromonas gingivalis (P. gingivalis), a periodontal pathogen, has been detected in the brains of AD patients and is associated with neurotoxicity. P. gingivalis triggers toll-like receptor (TLR-2) and TLR-4 signaling, leading to the activation of TNF-α and interleukine-1 (IL-1) through bacterial LPS and an increase in miRNA-9 expression (upregulation), ultimately alleviating inflammation (; ; ). LPS also induces the long non-coding RNA (lncRNA) MALAT1 in gingival fibroblasts, leading to pro-inflammatory states. Paradoxically, enhancing MALAT1 expression in AD brains has been linked to the inhibition of neuroinflammation (; ). Moreover, the lncRNA ANRIL, which is altered in periodontitis, is associated with AD-related neuroinflammation by binding to miRNA-125a, leading to its increased expression (). While both MALAT1 and ANRIL are influenced by periodontitis, MALAT1 appears to contribute to neuroprotection, whereas ANRIL has neurodegenerative consequences (). It is important to note that dysfunctions in olfaction can significantly impact mood and behavior. The miRNA-200 family plays a crucial role in olfactory neurogenesis, and there is an increasing interest in the role of the nasal microbiome in olfactory function and its potential connection to neurodegenerative disorders (). Some bacteria in the nasal cavity may have links to the central nervous system. For instance, Chlamydia pneumoniae, associated with sinusitis, has been found in the brains of Alzheimer’s disease patients. Additionally, Corynebacterium diphtheriae, known to produce diphtheria toxin, can enter the CNS, potentially contributing to sporadic AD (). Dysbiosis in the nasal microbiome may lead to inflammation, exacerbating neurodegeneration (,). Non-coding RNAs (ncRNAs), particularly miRNAs, may serve as key mediators in the nasal microbiota-brain axis. Studies have shown that elevated levels of miRNA-206 and inflammatory mediators are observed in human astrocytes exposed to LPS, and in early dementia patients, overexpression of miRNA-206 is associated with suppressed brain-derived neurotropic factor (BDNF), potentially aggravating neuropathogenesis in AD patients ().
6 Human virus infection and Alzheimer’s disease
The role of viruses in neurodegenerative diseases, including AD, is garnering attention. Non-coding RNAs, particularly miRNAs, are crucial in regulating viral replication and infection outcomes. Certain infectious agents, particularly those affecting the central nervous system (CNS), are associated with Alzheimer’s disease (AD) pathology, some of which can remain latent in the CNS and reactivate with age and stress, leading to subsequent inflammation, synaptic dysfunction, and neural loss ().
6.1 Human immunodeficiency viruses
In a study conducted in 2020, HIV-infected patients exhibited elevated BACE1 enzyme expression and increased production of Aβ (; Zhao and Lukiw, 2018a) in human astrocytes exposed to Tat, an early gene product of HIV-1 continually secreted from latently infected cells. This mechanism involved the upregulation of hypoxia-inducible factors-1-alfa (HIF-1α), leading to the formation of the lncRNA BACE1-antisense (AS/BACE1) RNA complex. Subsequently, the complex increased BACE1 enzyme activity (). Figure 4 illustrates how BACE1-AS functions as a competing endogenous RNA (ceRNA), sequestering miRNA-485-5p and relieving its inhibitory effect on BACE1 mRNA, ultimately resulting in increased BACE1 mRNA expression (; ; ). Research on lentiviruses in the CNS revealed that these viruses can induce the expression of miRNA-31, which significantly reduces Aβ deposition in the subiculum and hippocampus. This finding suggests a potential role for non-coding RNAs (ncRNAs) in Alzheimer’s disease (AD) neuropathology (). Contradictory effects of different lentiviruses on Alzheimer’s disease (AD) call for further comprehensive investigations.
Figure 4
6.2 Hepatitis B viruses
In patients infected with hepatitis B virus (HBV), a study observed a significant induction of miRNA-125b-5p in serum, which was associated with the persistence of the HBV infection. Another study revealed that the upregulation of miRNA-125b is linked to an increase in tau protein hyperphosphorylation in AD, which contributes to the progression of the disease ().
6.3 Severe acute respiratory coronavirus 2
In the context of viral infections, it has been reported that during Severe acute respiratory coronavirus 2 (SARS-CoV2) infection, miRNA-200c-3p disrupts the regulation of the angiotensin-converting enzyme (ACE), indirectly inhibiting viral infection (). Furthermore, a study in 2022 suggested that miR-200c suppression increases tau hyperphosphorylation by targeting 14-3-3y at the early-stage AD in a mouse model (5xFAD; ). These findings highlight the bidirectional impact of ncRNAs on microbes in disease development or suppression ().
6.4 Herpes simplex viruses
Herpes Simplex Virus type 1 (HSV-1) infection is recognized as a contributing factor to the progression of Alzheimer’s disease (AD). It is found in the latent form within the brains of many older individuals, leading to neural and glial cell damage and immune dysfunction. HSV-1 can enter the CNS without clinical symptoms, and its reactivation can accelerate the pathogenesis of AD (). HSV-1 expresses its own miRNAs abundantly during latency and has the capacity to manipulate host miRNAs to facilitate either replication or latency (). The co-evolution of the host and virus enables HSV-1 to hijack host cellular processes for its growth and survival. Non-coding RNAs, particularly miRNAs, play a crucial role in viral pathogenesis by balancing latency and reactivation in response to various stimuli. For example, cellular miRNA-101 targets mitochondrial ATP synthase, reducing the lytic replication of HSV-1 and promoting latency (Zheng et al., 2011). In contrast, miRNA-23a supports viral replication by inhibiting the host’s antiviral innate immune response (). Another study revealed that HSV-1 infection of human neuronal glial cells induced miRNA-146a, which targets key components of the arachidonic acid pathway and fumarate hydratase (FH), enabling HSV-1 to evade the complement system, exacerbating neuropathological changes in AD (; Zhao and Lukiw, 2018a; ). HSV-1 infection has also been associated with tau hyperphosphorylation, contributing to neurotoxicity in AD brains (). In summary, viral and cellular miRNAs and their interplay appear to play a significant role in viral latency and reactivation, thereby influencing virus replication and pathogenesis (). Consequently, miRNAs are strongly associated with viral-related pathological events ().
6.5 Human cytomegalovirus
Human cytomegalovirus (HCMV) causes severe disease, especially in individuals with compromised immune systems. It is linked to the early onset of systemic sclerosis and has the capability to enter the CNS, causing inflammation and histopathological changes in various brain cells. CMV-induced inflammation mediated by the host can exacerbate immunopathology and neuropathological symptoms (). Studies have reported several AD pathological hallmarks associated with neuro-invasive HCMV, including the accumulation of amyloid-beta (Aβ), astrogliosis, neuroinflammation, and neural damage. In vitro experiments have shown that HCMV can induce Aβ production and astrocyte reactivity, resembling AD pathological features (). HCMV encodes its own microRNAs (miRNAs) that target viral genes and host cellular ones, including immunomodulators. Additionally, it can modify cellular miRNAs to facilitate their replication (). HCMV can manipulate various cellular mechanisms to its advantage, affecting host metabolic pathways and cell apoptosis (; ). Notably, downregulation of the miRNA-199a/214 cluster has been observed in HCMV-infected cells (). In a study from 2020, miRNA-199a was found to decrease neuritin expression, contributing to AD progression in mouse models. Researchers noted significant miRNA-199a expression at the early stages of AD, suggesting its potential as a biomarker for early disease diagnosis ().
7 Conclusion
The early diagnosis of Alzheimer’s disease is critical for delaying or mitigating its progression. Non-coding RNAs (ncRNAs) present in blood circulation and the cerebrospinal fluid hold promise as reliable diagnostic biomarkers due to their stability and ease of detection. Moreover, ncRNAs have therapeutic potential, particularly in the preclinical stages of the disease. However, the development of effective drugs remains challenging due to a limited understanding of AD pathogenesis, and current drugs only offer symptomatic relief. Therefore, in-depth research into the causes of AD is essential. The regulatory role of ncRNAs in various human diseases, including the potential influence of microorganisms within the human body on host ncRNAs, presents a promising avenue for investigation. Studying the molecular basis of AD pathology, especially the mechanisms involving ncRNAs, is crucial for advancing rational treatment approaches. Accumulated amyloid-beta (Aβ), a hallmark of AD, can trigger microglia activation and subsequent neuroinflammation, with many ncRNAs, including miRNAs, playing key roles as modulators of neuroinflammation. Some ncRNAs also regulate enzymes involved in Aβ processing, highlighting their potential impact on AD pathology. Dysregulations of these ncRNAs, influenced by external factors such as viruses and bacteria, can significantly alter disease trajectories. Recent research has shed light on the role of gut and nasal microbiota in neurodegenerative diseases, emphasizing the role of ncRNAs in modulating immune responses and inflammation. Investigating the profiles of ncRNAs responsible for controlling pro-inflammatory genes associated with AD is essential for effective treatment or early disease diagnosis. Perturbations in neuroinflammation-related ncRNAs within various microbiome communities may lead to the dysregulation of specific signal transduction pathways, contributing to disease development. To improve treatment and diagnosis methodologies for Alzheimer’s disease, further research is needed to explore the roles of ncRNAs in regulating genes involved in the progression of the disease.
Statements
Author contributions
HM-P: Visualization, Writing – original draft, Conceptualization. MS: Supervision, Writing – review & editing, Conceptualization, Project administration. FJ: Data curation, Supervision, Writing – review & editing. HN: Data curation, Writing – review & editing. FM-G: Writing – review & editing, Supervision.
Acknowledgments
The authors gratefully acknowledge the support from contributors to this study.
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.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
Abu-IzneidT.AlHajriN.IbrahimA. M.JavedM. N.SalemK. M.PottooF. H.et al. (2021). Micro-RNAs in the regulation of immune response against SARS CoV-2 and other viral infections. J. Adv. Res.30, 133–145. doi: 10.1016/j.jare.2020.11.013
2
AdelmanJ. W.Rosas-RogersS.SchumacherM. L.MokryR. L.TerhuneS. S.EbertA. D. Human Cytomegalovirus Induces Significant Structural and Functional Changes in Terminally Differentiated Human Cortical Neurons. bioRxiv [Preprint]. (2023).
3
AhmedH.LeyrolleQ.KoistinenV.KärkkäinenO.LayéS.DelzenneN.et al. (2022). Microbiota-derived metabolites as drivers of gut-brain communication. Gut Microbes14:2102878. doi: 10.1080/19490976.2022.2102878
4
AlqahtaniT.DeoreS. L.KideA. A.ShendeB. A.SharmaR.Dadarao ChakoleR.et al. (2023). Mitochondrial dysfunction and oxidative stress in Alzheimer’s disease, and Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis-an updated review. Mitochondrion71, 83–92. doi: 10.1016/j.mito.2023.05.007
5
AlvarezG.AldudoJ.AlonsoM.SantanaS.ValdiviesoF. (2012). Herpes simplex virus type 1 induces nuclear accumulation of hyperphosphorylated tau in neuronal cells. J. Neurosci. Res.90, 1020–1029. doi: 10.1002/jnr.23003
6
Aragón-GonzálezA.ShawP. J.FerraiuoloL. (2022). Blood-brain barrier disruption and its involvement in neurodevelopmental and neurodegenerative disorders. Int. J. Mol. Sci.23:5271. doi: 10.3390/ijms232315271
7
ArakiW. (2023). Aβ oligomer toxicity-reducing therapy for the prevention of Alzheimer's disease: importance of the Nrf2 and PPARγ pathways. Cells12:1386. doi: 10.3390/cells12101386
8
ArzuaT.JiangC.YanY.BaiX. (2021). The importance of non-coding RNAs in environmental stress-related developmental brain disorders: a systematic review of evidence associated with exposure to alcohol, anesthetic drugs, nicotine, and viral infections. Neurosci. Biobehav. Rev.128, 633–647. doi: 10.1016/j.neubiorev.2021.06.033
9
BangasserD. A.DongH.CarrollJ.PlonaZ.DingH.RodriguezL.et al. (2017). Corticotropin-releasing factor overexpression gives rise to sex differences in Alzheimer's disease-related signaling. Mol. Psychiatry22, 1126–1133. doi: 10.1038/mp.2016.185
10
BarandouziZ. A.StarkweatherA. R.HendersonW. A.GyamfiA.CongX. S. (2020). Altered composition of gut microbiota in depression: a systematic review. Front. Psych.11:541. doi: 10.3389/fpsyt.2020.00541
11
BarichelloT.GenerosoJ. S.MilioliG.EliasS. G.TeixeiraA. L. (2013). Pathophysiology of bacterial infection of the central nervous system and its putative role in the pathogenesis of behavioral changes. Braz J Psychiatry.35, 81–87. doi: 10.1016/j.rbp.2012.11.003
12
Barros-ViegasA. T.CarmonaV.FerreiroE.GuedesJ.CardosoA. M.CunhaP.et al. (2020). miRNA-31 improves cognition and abolishes amyloid-β pathology by targeting APP and BACE1 in an animal model of Alzheimer's disease. Mol Ther Nucleic Acids.19, 1219–1236. doi: 10.1016/j.omtn.2020.01.010
13
BashirY.KhanA. U. (2022). The interplay between the gut-brain axis and the microbiome: a perspective on psychiatric and neurodegenerative disorders. Front. Neurosci.16:1030694. doi: 10.3389/fnins.2022.1030694
14
Bernabeu-ZornozaA.CoronelR.PalmerC.MartínA.López-AlonsoV.ListeI. (2022). Neurogenesis is increased in human neural stem cells by Aβ40 peptide. Int. J. Mol. Sci.23:5820. doi: 10.3390/ijms23105820
15
BernierA.SaganS. M. (2018). The diverse roles of microRNAs at the host−Virus Interface. Viruses10:440. doi: 10.3390/v10080440
16
BhattacharyyaN.PandeyV.BhattacharyyaM.DeyA. (2021). Regulatory role of long non coding RNAs (lncRNAs) in neurological disorders: from novel biomarkers to promising therapeutic strategies. Asian J Pharm Sci.16, 533–550. doi: 10.1016/j.ajps.2021.02.006
17
BostanciklioğluM. (2019). The role of gut microbiota in pathogenesis of Alzheimer's disease. J. Appl. Microbiol.127, 954–967. doi: 10.1111/jam.14264
18
CandidoS.LupoG.PennisiM.BasileM. S.AnfusoC. D.PetraliaM. C.et al. (2019). The analysis of miRNA expression profiling datasets reveals inverse microRNA patterns in glioblastoma and Alzheimer's disease. Oncol. Rep.42, 911–922. doi: 10.3892/or.2019.7215
19
Canseco-RodriguezA.MasolaV.AlipertiV.Meseguer-BeltranM.DonizettiA.Sanchez-PerezA. M. (2022). Long non-coding RNAs, extracellular vesicles and inflammation in Alzheimer's disease. Int. J. Mol. Sci.23:3171. doi: 10.3390/ijms232113171
20
CaoM.LiH.ZhaoJ.CuiJ.HuG. (2019). Identification of age-and gender-associated long noncoding RNAs in the human brain with Alzheimer's disease. Neurobiol. Aging81, 116–126. doi: 10.1016/j.neurobiolaging.2019.05.023
21
CarthewR. W.SontheimerE. J. (2009). Origins and mechanisms of miRNAs and siRNAs. Cells136, 642–655. doi: 10.1016/j.cell.2009.01.035
22
Castro-AldreteL.MoserM. V.PutignanoG.FerrettiM. T.Schumacher DimechA.SantuccioneC. A. (2023). Sex and gender considerations in Alzheimer's disease: the Women's brain project contribution. Front. Aging Neurosci.15:1105620. doi: 10.3389/fnagi.2023.1105620
23
ChandraS.SisodiaS. S.VassarR. J. (2023). The gut microbiome in Alzheimer's disease: what we know and what remains to be explored. Mol. Neurodegener.18:9. doi: 10.1186/s13024-023-00595-7
24
ChoiP. S.ZakharyL.ChoiW. Y.CaronS.Alvarez-SaavedraE.MiskaE. A.et al. (2008). Members of the miRNA-200 family regulate olfactory neurogenesis. Neuron57, 41–55. doi: 10.1016/j.neuron.2007.11.018
25
Cokarić BrdovčakM.ZubkovićA.JurakI. (2018). Herpes simplex virus 1 deregulation of host MicroRNAs. Noncoding. RNA4:36. doi: 10.3390/ncrna4040036
26
DasT.DasT. K.KhodarkovskayaA.DashS. (2021). Non-coding RNAs and their bioengineering applications for neurological diseases. Bioengineered.12, 11675–11698. doi: 10.1080/21655979.2021.2003667
27
DasS.VasanjiA.PellettP. E. (2007). Three-dimensional structure of the human cytomegalovirus cytoplasmic virion assembly complex includes a reoriented secretory apparatus. J. Virol.81, 11861–11869. doi: 10.1128/JVI.01077-07
28
DattaM.StaszewskiO.RaschiE.FroschM.HagemeyerN.TayT. L.et al. (2018). Histone deacetylases 1 and 2 regulate microglia function during development, homeostasis, and neurodegeneration in a context-dependent manner. Immunity48, 514–29.e6. doi: 10.1016/j.immuni.2018.02.016
29
DhuruvasanK.SivasubramanianG.PellettP. E. (2011). Roles of host and viral microRNAs in human cytomegalovirus biology. Virus Res.157, 180–192. doi: 10.1016/j.virusres.2010.10.011
30
DominyS. S.LynchC.ErminiF.BenedykM.MarczykA.KonradiA.et al. (2019). Porphyromonas gingivalis in Alzheimer's disease brains: evidence for disease causation and treatment with small-molecule inhibitors. Sci. Adv.5:eaau3333. doi: 10.1126/sciadv.aau3333
31
DorszewskaJ.PrendeckiM.OczkowskaA.DezorM.KozubskiW. (2016). Molecular basis of familial and sporadic Alzheimer's disease. Curr. Alzheimer Res.13, 952–963. doi: 10.2174/1567205013666160314150501
32
DuanX.ZohaibA.LiY.ZhuB.YeJ.WanS.et al. (2015). miR-206 modulates lipopolysaccharide-mediated inflammatory cytokine production in human astrocytes. Cell. Signal.27, 61–68. doi: 10.1016/j.cellsig.2014.10.006
33
El HayekL.KhalifehM.ZibaraV.Abi AssaadR.EmmanuelN.KarnibN.et al. (2019). Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF). J. Neurosci.39, 2369–2382. doi: 10.1523/JNEUROSCI.1661-18.2019
34
FišarZ. (2022). Linking the amyloid, tau, and mitochondrial hypotheses of Alzheimer's disease and identifying promising drug targets. Biomol. Ther.12:1676. doi: 10.3390/biom12111676
35
FuX. D. (2014). Non-coding RNA: a new frontier in regulatory biology. Natl. Sci. Rev.1, 190–204. doi: 10.1093/nsr/nwu008
36
GholamiL.Ghafouri-FardS.MirzajaniS.Arsang-JangS.TaheriM.DehbaniZ.et al. (2020). The lncRNA ANRIL is down-regulated in peripheral blood of patients with periodontitis. Noncoding RNA Res.5, 60–66. doi: 10.1016/j.ncrna.2020.04.001
37
GomesA. Q.NolascoS.SoaresH. (2013). Non-coding RNAs: multi-tasking molecules in the cell. Int. J. Mol. Sci.14, 16010–16039. doi: 10.3390/ijms140816010
38
GuoT.NobleW.HangerD. P. (2017). Roles of tau protein in health and disease. Acta Neuropathol.133, 665–704. doi: 10.1007/s00401-017-1707-9
39
GurtanA. M.SharpP. A. (2013). The role of miRNAs in regulating gene expression networks. J. Mol. Biol.425, 3582–3600. doi: 10.1016/j.jmb.2013.03.007
40
HaoY.XieB.FuX.XuR.YangY. (2022). New insights into lncRNAs in Aβ Cascade hypothesis of Alzheimer's disease. Biomol. Ther.12:1802. doi: 10.3390/biom12121802
41
HasavciD.BlankT. (2022). Age-dependent effects of gut microbiota metabolites on brain resident macrophages. Front. Cell. Neurosci.16:944526. doi: 10.3389/fncel.2022.944526
42
HillJ. M.ZhaoY.ClementC.NeumannD. M.LukiwW. J. (2009). HSV-1 infection of human brain cells induces miRNA-146a and Alzheimer-type inflammatory signaling. Neuroreport20, 1500–1505. doi: 10.1097/WNR.0b013e3283329c05
43
HouK.WuZ. X.ChenX. Y.WangJ. Q.ZhangD.XiaoC.et al. (2022). Microbiota in health and diseases. Signal Transduct. Target. Ther.7:135. doi: 10.1038/s41392-022-00974-4
44
HuangF.WuX. (2021). Brain neurotransmitter modulation by gut microbiota in anxiety and depression. Front. Cell Dev. Biol.9:649103. doi: 10.3389/fcell.2021.649103
45
IshidaN.IshiharaY.IshidaK.TadaH.Funaki-KatoY.HagiwaraM.et al. (2017). Periodontitis induced by bacterial infection exacerbates features of Alzheimer's disease in transgenic mice. NPJ Aging Mech Dis.3:15. doi: 10.1038/s41514-017-0015-x
46
ItzhakiR. F.LatheR.BalinB. J.BallM. J.BearerE. L.BraakH.et al. (2016). Microbes and Alzheimer's disease. J. Alzheimers Dis.51, 979–984. doi: 10.3233/JAD-160152
47
JohnsonD.LetchumananV.ThumC. C.ThurairajasingamS.LeeL. H. (2023). A microbial-based approach to mental health: the potential of probiotics in the treatment of depression. Nutrients15:1382. doi: 10.3390/nu15061382
48
KaurH.BoseC.MandeS. S. (2019). Tryptophan metabolism by gut microbiome and gut-brain-Axis: an in silico analysis. Front. Neurosci.13:1365. doi: 10.3389/fnins.2019.01365
49
KhanS.BarveK. H.KumarM. S. (2020). Recent advancements in pathogenesis, diagnostics and treatment of Alzheimer's disease. Curr. Neuropharmacol.18, 1106–1125. doi: 10.2174/1570159X18666200528142429
50
KimK. W. (2019). PIWI proteins and piRNAs in the nervous system. Mol. Cells42, 828–835. doi: 10.14348/molcells.2019.0241
51
KrstanovićF.BrittW. J.JonjićS.BrizićI. (2021). Cytomegalovirus infection and inflammation in developing brain. Viruses13:1078. doi: 10.3390/v13061078
52
LeblhuberF.EhrlichD.SteinerK.GeislerS.FuchsD.LanserL.et al. (2021). The immunopathogenesis of Alzheimer's disease is related to the composition of gut microbiota. Nutrients13:361. doi: 10.3390/nu13020361
53
LengS. X.KamilJ.PurdyJ. G.LemmermannN. A.ReddehaseM. J.GoodrumF. D. (2017). Recent advances in CMV tropism, latency, and diagnosis during aging. Geroscience.39, 251–259. doi: 10.1007/s11357-017-9985-7
54
LiF.HearnM.BennettL. E. (2021). The role of microbial infection in the pathogenesis of Alzheimer's disease and the opportunity for protection by anti-microbial peptides. Crit. Rev. Microbiol.47, 240–253. doi: 10.1080/1040841X.2021.1876630
55
LiX.WangH.ZhangY.ZhangJ.QiS.ZhangY.et al. (2019). Overexpression of lncRNA H19 changes basic characteristics and affects immune response of bovine mammary epithelial cells. PeerJ.7:e6715. doi: 10.7717/peerj.8265
56
LiuY.ChengX.LiH.HuiS.ZhangZ.XiaoY.et al. (2022). Non-coding RNAs as novel regulators of neuroinflammation in Alzheimer's disease. Front. Immunol.13:908076. doi: 10.3389/fimmu.2022.947136
57
LombardiG.CrescioliG.CavedoE.LucenteforteE.CasazzaG.BellatorreA. G.et al. (2020). Structural magnetic resonance imaging for the early diagnosis of dementia due to Alzheimer's disease in people with mild cognitive impairment. Cochrane Database Syst. Rev.3:Cd009628. doi: 10.1002/14651858.CD009628.pub2
58
LukiwW. J.ArceneauxL.LiW.BondT.ZhaoY. (2021). Gastrointestinal (GI)-tract microbiome derived neurotoxins and their potential contribution to inflammatory neurodegeneration in Alzheimer's disease (AD). J Alzheimers Dis Parkinsonism.11:525. PMID:
59
LuoQ.ChenY. (2016). Long noncoding RNAs and Alzheimer's disease. Clin. Interv. Aging11, 867–872. doi: 10.2147/CIA.S107037
60
LyketsosC. G.CarrilloM. C.RyanJ. M.KhachaturianA. S.TrzepaczP.AmatniekJ.et al. (2011). Neuropsychiatric symptoms in Alzheimer's disease. Alzheimers Dement.7, 532–539. doi: 10.1016/j.jalz.2011.05.2410
61
MaL.BajicV. B.ZhangZ. (2013). On the classification of long non-coding RNAs. RNA Biol.10, 925–933. doi: 10.4161/rna.24604
62
MielcarskaM. B.SkowrońskaK.WyżewskiZ.TokaF. N. (2021). Disrupting neurons and glial cells oneness in the brain-the possible causal role of herpes simplex virus type 1 (HSV-1) in Alzheimer's disease. Int. J. Mol. Sci.23:242. doi: 10.3390/ijms23010242
63
MiguelV.LamasS.Espinosa-DiezC. (2020). Role of non-coding-RNAs in response to environmental stressors and consequences on human health. Redox Biol.37:101580:101580. doi: 10.1016/j.redox.2020.101580
64
MoloneyG. M.O’Leary OFSalvo-RomeroE.DesbonnetL.ShanahanF.DinanT. G.et al. (2017). Microbial regulation of hippocampal miRNA expression: implications for transcription of kynurenine pathway enzymes. Behav. Brain Res.334, 50–54. doi: 10.1016/j.bbr.2017.07.026
65
NiY. Q.XuH.LiuY. S. (2022). Roles of long non-coding RNAs in the development of aging-related neurodegenerative diseases. Front. Mol. Neurosci.15:844193. doi: 10.3389/fnmol.2022.844193
66
NiuY.MoD.QinL.WangC.LiA.ZhaoX.et al. (2011). Lipopolysaccharide-induced miR-1224 negatively regulates tumour necrosis factor-α gene expression by modulating Sp1. Immunology133, 8–20. doi: 10.1111/j.1365-2567.2010.03374.x
67
ParkH.LeeY. B.ChangK. A. (2022). miR-200c suppression increases tau hyperphosphorylation by targeting 14-3-3γ in early stage of 5xFAD mouse model of Alzheimer's disease. Int. J. Biol. Sci.18, 2220–2234. doi: 10.7150/ijbs.66604
68
PiedadeD.Azevedo-PereiraJ. M. (2016). The role of microRNAs in the pathogenesis of herpesvirus infection. Viruses8:156. doi: 10.3390/v8060156
69
PlutaR.Ułamek-KoziołM.JanuszewskiS.CzuczwarS. J. (2020). Gut microbiota and pro/prebiotics in Alzheimer's disease. Aging12, 5539–5550. doi: 10.18632/aging.102930
70
RomanenkoM.KholinV.KoliadaA.VaisermanA. (2021). Nutrition, gut microbiota, and Alzheimer's disease. Front. Psych.12:712673. doi: 10.3389/fpsyt.2021.712673
71
RosaJ. M.FormoloD. A.YuJ.LeeT. H.YauS. Y. (2022). The role of MicroRNA and microbiota in depression and anxiety. Front. Behav. Neurosci.16:828258. doi: 10.3389/fnbeh.2022.828258
72
RuJ.SunH.FanH.WangC.LiY.LiuM.et al. (2014). MiR-23a facilitates the replication of HSV-1 through the suppression of interferon regulatory factor 1. PloS One9:e114021. doi: 10.1371/journal.pone.0114021
73
Ruiz-OreraJ.AlbàM. M. (2019). Conserved regions in long non-coding RNAs contain abundant translation and protein-RNA interaction signatures. NAR Genom Bioinform.1:e2. doi: 10.1093/nargab/lqz002
74
RyuI. S.KimD. H.ChoH. J.RyuJ. H. (2023). The role of microRNA-485 in neurodegenerative diseases. Rev. Neurosci.34, 49–62. doi: 10.1515/revneuro-2022-0039
75
SampsonT. R.DebeliusJ. W.ThronT.JanssenS.ShastriG. G.IlhanZ. E.et al. (2016). Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease. Cells167, 1469–1480. doi: 10.1016/j.cell.2016.11.018
76
SatoK.TakayamaK. I.InoueS. (2023). Role of piRNA biogenesis and its neuronal function in the development of neurodegenerative diseases. Front. Aging Neurosci.15:1157818. doi: 10.3389/fnagi.2023.1157818
77
SayadA.NajafiS.HussenB. M.AbdullahS. T.MovahedpourA.TaheriM.et al. (2022). The emerging roles of the β-secretase BACE1 and the long non-coding RNA BACE1-AS in human diseases: a focus on neurodegenerative diseases and cancer. Front. Aging Neurosci.14:853180. doi: 10.3389/fnagi.2022.853180
78
SilS.HuG.LiaoK.NiuF.CallenS.PeriyasamyP.et al. (2020). HIV-1 tat-mediated astrocytic amyloidosis involves the HIF-1α/lncRNA BACE1-AS axis. PLoS Biol.18:e3000660. doi: 10.1371/journal.pbio.3000660
79
SilzerT. K.PathakG. A.PhillipsN. R. (2020). Mitochondrial tRNA methylation in Alzheimer's disease and progressive supranuclear palsy. BMC Med. Genet.13:71. doi: 10.1186/s12920-020-0727-9
80
SinghA. K.RoogeS. B.VarshneyA.VasudevanM.BhardwajA.VenugopalS. K.et al. (2018). Global microRNA expression profiling in the liver biopsies of hepatitis B virus-infected patients suggests specific microRNA signatures for viral persistence and hepatocellular injury. Hepatology67, 1695–1709. doi: 10.1002/hep.29690
81
SlotaJ. A.BoothS. A. (2019). MicroRNAs in neuroinflammation: implications in disease pathogenesis, biomarker discovery and therapeutic applications. Noncoding RNA5:35. doi: 10.3390/ncrna5020035
82
SochockaM.Donskow-ŁysoniewskaK.DinizB. S.KurpasD.BrzozowskaE.LeszekJ. (2019). The gut microbiome alterations and inflammation-driven pathogenesis of Alzheimer's disease-a critical review. Mol. Neurobiol.56, 1841–1851. doi: 10.1007/s12035-018-1188-4
83
SodagarH.AlipourS.HassaniS.AzizS. G.AnsariM. H. K.AsghariR. (2022). The role of microRNAs in COVID-19 with a focus on miR-200c. J Circ Biomark.11, 14–23. doi: 10.33393/jcb.2022.2356
84
SongD.LiG.HongY.ZhangP.ZhuJ.YangL.et al. (2020). miR-199a decreases Neuritin expression involved in the development of Alzheimer's disease in APP/PS1 mice. Int. J. Mol. Med.46, 384–396. doi: 10.3892/ijmm.2020.4602
85
StatelloL.GuoC.-J.ChenL.-L.HuarteM. (2021). Gene regulation by long non-coding RNAs and its biological functions. Nat. Rev. Mol. Cell Biol.22, 96–118. doi: 10.1038/s41580-020-00315-9
86
SwerN. M.VenkideshB. S.MuraliT. S.MumbrekarK. D. (2023). Gut microbiota-derived metabolites and their importance in neurological disorders. Mol. Biol. Rep.50, 1663–1675. doi: 10.1007/s11033-022-08038-0
87
TangW.ZhuH.FengY.GuoR.WanD. (2020). The impact of gut microbiota disorders on the blood-brain barrier. Infect Drug Resist.13, 3351–3363. doi: 10.2147/IDR.S254403
88
ThangaleelaS.SivamaruthiB. S.KesikaP.BharathiM.ChaiyasutC. (2022a). Nasal microbiota, olfactory health, neurological disorders and aging: a review. Microorganisms.10:1405. doi: 10.3390/microorganisms10071405
89
ThangaleelaS.SivamaruthiB. S.KesikaP.ChaiyasutC. (2022b). Role of probiotics and diet in the Management of Neurological Diseases and Mood States: a review. Microorganisms.10:2268. doi: 10.3390/microorganisms10112268
90
ValenzaM.ScuderiC. (2022). How useful are biomarkers for the diagnosis of Alzheimer's disease and especially for its therapy?Neural Regen. Res.17, 2205–2207. doi: 10.4103/1673-5374.335791
91
WangG. Q.WangY.XiongY.ChenX. C.MaM. L.CaiR.et al. (2016). Sirt1 AS lncRNA interacts with its mRNA to inhibit muscle formation by attenuating function of miR-34a. Sci. Rep.6:21865.
92
WuW.LeeI.SprattH.FangX.BaoX. (2021). tRNA-derived fragments in Alzheimer's disease: implications for new disease biomarkers and neuropathological mechanisms. J. Alzheimers Dis.79, 793–806. doi: 10.3233/JAD-200917
93
XueX.FengT.YaoS.WolfK. J.LiuC. G.LiuX.et al. (2011). Microbiota downregulates dendritic cell expression of miR-10a, which targets IL-12/IL-23p40. J. Immunol.187, 5879–5886. doi: 10.4049/jimmunol.1100535
94
ZhangY.GengR.TuQ. (2021). Gut microbial involvement in Alzheimer's disease pathogenesis. Aging13, 13359–13371. doi: 10.18632/aging.202994
95
ZhangM.HeP.BianZ. (2021). Long noncoding RNAs in neurodegenerative diseases: pathogenesis and potential implications as clinical biomarkers. Front. Mol. Neurosci.14:685143. doi: 10.3389/fnmol.2021.685143
96
ZhangP.WuW.ChenQ.ChenM. (2019). Non-coding RNAs and their integrated networks. J. Integr. Bioinform.16:27. doi: 10.1515/jib-2019-0027
97
ZhaoY.LukiwW. J. (2018a). Microbiome-mediated upregulation of MicroRNA-146a in sporadic Alzheimer’s disease. Front. Neurol.9:649103. doi: 10.3389/fneur.2018.00145
98
ZhaoY.LukiwW. J. (2018b). Bacteroidetes neurotoxins and inflammatory neurodegeneration. Mol. Neurobiol.55, 9100–9107. doi: 10.1007/s12035-018-1015-y
99
ZhaoY.WangZ.MaoY.LiB.ZhuY.ZhangS.et al. (2020). NEAT1 regulates microtubule stabilization via FZD3/GSK3β/P-tau pathway in SH-SY5Y cells and APP/PS1 mice. Aging12, 23233–23250. doi: 10.18632/aging.104098
100
ZhaoY.ZengY.ZengD.WangH.ZhouM.SunN.et al. (2021). Probiotics and MicroRNA: their roles in the host–microbe interactions. Front. Microbiol.11:604462. doi: 10.3389/fmicb.2020.604462
101
ZhengS. Q.LiY. X.ZhangY.LiX.TangH. (2011). MiR-101 regulates HSV-1 replication by targeting ATP5B. Antiviral Res.89, 219–226. doi: 10.1016/j.antiviral.2011.01.008
102
ZhouS.YuX.WangM.MengY.SongD.YangH.et al. (2021). Long non-coding RNAs in pathogenesis of neurodegenerative diseases. Front. Cell Dev. Biol.9:719247. doi: 10.3389/fcell.2021.807419
Summary
Keywords
Alzheimer’s disease, non-coding RNAs, gut microbiome, viral disease, gut–brain axis, neurodegenerative disorders
Citation
Mohammadi-Pilehdarboni H, Shenagari M, Joukar F, Naziri H and Mansour-Ghanaei F (2024) Alzheimer’s disease and microorganisms: the non-coding RNAs crosstalk. Front. Cell. Neurosci. 17:1256100. doi: 10.3389/fncel.2023.1256100
Received
10 July 2023
Accepted
25 October 2023
Published
05 January 2024
Volume
17 - 2023
Edited by
Nouha Bouayed Abdelmoula, University of Sfax, Tunisia
Reviewed by
Sabrina Petralla, Heidelberg University, Germany; Saivageethi Nuthikattu, University of California, Davis, United States
Updates
Copyright
© 2024 Mohammadi-Pilehdarboni, Shenagari, Joukar, Naziri and Mansour-Ghanaei.
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) and the copyright owner(s) 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: Mohammad Shenagari, shenagari@gmail.comFarahnaz Joukar, farajov@gmail.com
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.