miR-137: A therapeutic candidate or a key molecular regulator in Alzheimer's disease?

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder driven by amyloid-β accumulation, tau pathology, and synaptic dysfunction. Recent studies highlight miR-137, a brain-enriched microRNA, as a pivotal regulator of AD pathogenesis. This review synthesizes evidence that miR-137 modulates amyloid-β production, tau phosphorylation, synaptic plasticity, and neuroinflammation, while also preserving mitochondrial function and mitigating oxidative stress. Notably, circulating miR-137 levels correlate with AD progression, offering promise as a non-invasive diagnostic biomarker. Beyond diagnostics, miR-137's ability to target multiple AD-related pathways positions it as a novel therapeutic candidate for neuroprotection. Hence, miR-137 serves as both a biomarker and therapeutic target, offering promising strategies to slow AD progression and improve outcomes. Our bioinformatic analyses further identify miR-137-regulated genes and disrupted networks, underscoring its central role in AD. By bridging molecular mechanisms and clinical potential, miR-137-based strategies could transform AD management, addressing both pathological hallmarks and cognitive decline. Hence, this review article consolidates evidence of miR-137's multifaceted functions in AD, encouraging further investigation into its molecular mechanisms and translational potential to address this pathogenic condition.

Keywords

Alzheimer's disease biomarker miR-137 target treatment

Introduction

Alzheimer's disease (AD) is a progressive, age-associated neurodegenerative disorder. It is marked by the abnormal accumulation of amyloid-β (Aβ) plaques and tau protein tangles in the brain. These pathological features disrupt neural communication, leading to neuronal death, brain atrophy, and cognitive decline.^1,2 Prevalence of AD is quite high, ∼47 million individuals worldwide are affected, with 15% of Americans aged 68 or older.³ Unfortunately, it is a growing public health crisis in China, which hosts the largest population of individuals affected by this condition globally.⁴ As of 2019, there were ∼10 million cases of AD reported in China, with this number expected to rise dramatically to 28 million by 2025.⁵ It is a growing challenge due to its prevalence and societal impact. Despite understanding amyloid aggregation extracellular, while tau deposits are predominantly intracellular, and neuroinflammation, its pathogenesis remains unclear.^6–8

microRNAs (miRNAs) control gene expression by binding to target mRNAs, resulting in either translation inhibition or mRNA degradation. miRNAs regulate pathophysiological processes such as inflammation, oxidative stress, synaptic plasticity, and apoptosis. Their dysregulation is linked to neurodegenerative diseases like Alzheimer's,^9–11 Parkinson's,¹² and Huntington's,¹³ making them valuable as biomarkers and therapeutic targets. While numerous miRNAs have been identified as potential therapeutic targets,¹⁴ but, miR-137, commonly downregulated in AD, is crucial for maintaining brain health by regulating inflammation, mitochondrial activity, and neuronal survival. Its diverse roles make it a strong candidate for multi-targeted therapeutic approaches in neurodegenerative conditions like AD.^15,16 Hence, this review and computational prediction analyses focus on miR-137's involvement in AD progression, highlighting its potential for enhancing molecular understanding and advancing targeted therapeutic strategies.

Role and molecular mechanisms of miR-137 in AD

Expression regulation of miR-137 in AD

miR-137 is predominantly expressed in the midbrain cortical tissue and hippocampus, areas heavily impacted by AD.^17–19 Studies have revealed that miR-137 is significantly downregulated in the frontal cortex of AD patients and in mice model.²⁰ Notably, reduced miR-137 levels have also been observed in the serum of both AD patients and animal models, indicating its potential as a non-invasive diagnostic tool.^21,22 Moreover, its hippocampal delivery in an AD model improved memory and reduced apoptosis by regulating Cdc42, vital for neuronal survival.²³ Another study highlighted the role of aerobic physical exercise in upregulating miR-137 expression, which improved memory performance and synaptic function.^24,25 Together, these findings suggest that miR-137 acts as a neuroprotective agent and holds a therapeutic target for mitigating AD progression. Similarly, long non-coding RNAs (lncRNAs), SNHG19 overexpressed in AD, disrupts the miR-137/TNFAIP1 axis, impairing AKT/CREB signaling and exacerbating neurotoxicity. Knockdown of SNHG19 reverses these harmful effects, underscoring the therapeutic potential of targeting miR-137-related pathways to alleviate AD progression.²⁶ Moreover, overexpression of miR-137-3p improved memory in rats by reducing monoacylglycerol lipase (MAGL) mRNA levels. MAGL, which breaks down the endocannabinoid 2-arachidonylglycerol, is linked to disease progression in the hippocampus of AD patients.²⁷ Furthermore, Table 1 summarizes the reported data on miR-137 for the management of AD.

Table 1.

Summary of miR-137 studies in AD.

Study Material	Assay Used	Target Genes	Biological Pathways	Outcome	References
Human neuroblastoma SH-SY5Y cells, APP/PS1 transgenic mice	Western blot, luciferase assay	CACNA1C	Tau hyperphosphorylation, calcium signaling	miR-137 inhibits tau hyperphosphorylation and regulates CACNA1C expression	²⁸
SH-SY5Y cells treated with Aβ25-35	Dual luciferase assay	TNFAIP1	Epigenetic regulation	SNHG19/miR-137 axis modulates cytotoxicity	²⁶
AD mouse model	miR-137 agomir	USP30	Ubiquitin signaling	Improved spatial memory and cognition	²⁹
Human brain tissues	Microarray	SPT	Ceramide synthesis, amyloid β generation	Loss of miR-137 increases SPT and amyloid β levels	²⁰
SH-SY5Y cells	Luciferase reporter assay	NEUROD4	Inflammation, oxidative stress	miR-137 reduces inflammation and oxidative stress	³⁰
Graphene oxide nanobiosensor	Fluorescence spectrophotometry	Not specified	Biomarker detection	Sensitive detection of miR-137 in blood	³¹

Inflammatory response mediated by miR-137 in AD

miR-137 modulates neuroinflammation by antagonizing the expression of pleiotrophin (PTN), a proinflammatory neurotrophic factor that is enriched in senile plaques in AD brains.³² Additionally, miR-137 can influence microglial function, which is crucial in the inflammatory process, by downregulating the expression of Jun dimerization protein 2 (Jdp2), a transcription factor involved in controlling oxidative stress and inflammatory responses.³³ Furthermore, Aβ_1–42 induces inflammation, tau phosphorylation, and USP30 upregulation in SH-SY5Y cells. miR-137-5p mimics reduce these effects, but USP30 overexpression reverses the protection. In AD mice, miR-137-5p agomir lowered Aβ_1–42, USP30, and tau phosphorylation, preserved neurons, and improved cognition, indicating miR-137-5p acts via USP30 suppression.²⁹ Moreover, miR-137 also regulates inflammatory responses TNFAIP1 and NF-κB pathways, alleviating Aβ-induced neurotoxicity.³⁴ Hence, investigating its interplay with lncRNAs and related pathways could enable novel treatments to mitigate AD pathology and improve cognitive function. To date, there are limited data on pre-clinical, and patent on miR-137 for the management of AD as listed in Table 2.

Table 2.

Preclinical and patents of miR-137 for the management of AD.

Preclinical Studies of miR-137 in AD
Study Material	Model	Outcome	References
APP/PS1 transgenic mice	Mouse model	miR-137 inhibits tau hyperphosphorylation and improves spatial memory	²⁸
SH-SY5Y cells	Cell model	miR-137 regulates CACNA1C and reduces tau phosphorylation	²⁸
AD mouse model	Mouse model	miR-137 agomir improves cognition and targets USP30	²⁹
Human serum	Biosensor	Sensitive detection of miR-137 as a biomarker	³⁵
Patents Involving miR-137 for AD (2018–2024)
Patent/Disclosure	Description		References
Biosensor for miR-137 detection	Graphene oxide-based biosensor for early AD diagnosis		³⁵
Therapeutic targeting of miR-137	miR-137 agomir for cognitive improvement in AD models		²⁹

miR-137 delays Aβ protein deposition

The imbalance between Aβ production and clearance is central to AD pathogenesis according to amyloid hypothesis. Studies highlight a strong association between ceramide and Aβ.³⁶ Ceramide, a key constituent of lipid rafts, facilitates amyloidogenesis by stabilizing β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), promoting Aβ formation and neuroinflammatory plaques.^37,38 Elevated ceramide levels in the AD cortex mislocalize γ-secretase and BACE1, enhancing lipid raft assembly and Aβ production.^39,40 Furthermore, ceramide induces reactive oxygen species (ROS), apoptosis, and neuronal death.⁴¹ miR-137 regulates the SPTLC1 gene, which encodes a key enzyme in ceramide biosynthesis, leading to elevated ceramide levels and increased Aβ production characteristic of sporadic AD.²⁰

It has also been reported that ceramide accumulation perpetuates a vicious cycle, activating NADPH oxidase, depleting glutathione, and increasing ROS levels, which further amplifies ceramide and Aβ production.⁴² Additionally, miR-137 protects neurons from Aβ-induced neurotoxicity in AD by targeting and suppressing extracellular signal-regulated kinases 1/2 (ERK1/2), reducing apoptosis and improving cell survival.⁴³ Thus, miR-137 downregulation accelerates Aβ production, inflammation, synaptic loss, and neuronal death, highlighting its therapeutic potential to delay AD progression as shown in Figure 1.

Figure 1.

Therapeutic potential of miR-137 in different pathways of AD pathogeneses. This figure highlights the pathological mechanisms of AD and the therapeutic potential of miR-137. Aβ peptides activate BACE1, increasing ceramide production, neuroinflammation, and neuronal damage. Aβ oligomers disrupt calcium homeostasis, causing synaptic degeneration and apoptosis. CDK5 hyperactivation leads to tau hyperphosphorylation and memory deficits, while circadian rhythm disruptions worsen mitochondrial dysfunction and cognitive decline. Inflammation of AMPAR and disrupted glutamate signaling impair synaptic plasticity and long term potentiation (LTP). miR-137 plays a critical role in downregulating these pathways, offering potential therapeutic benefits for AD management by mitigating neuronal damage and cognitive deficits.

miR-137 affects Ca²⁺ homeostasis and tau hyperphosphorylation

Ca²⁺ is essential for neuronal function, dysregulated Ca²⁺ signaling contributes to neuronal dysfunction and degeneration in AD. The CACNA1C, encoding the alpha 1C subunit of the CaV1.2 voltage-gated calcium channel, regulates intracellular Ca²⁺ levels at postsynaptic sites.^44–46 Over-activation of CaV1.2 results in excessive Ca²⁺ influx, increasing neuronal damage and the risk of AD.⁴⁷ miR-137 regulate Ca²⁺ homeostasis and tau hyperphosphorylation, both critical in AD pathology. miR-137 directly targets CACNA1C, reducing its expression. In AD models, decreased miR-137 levels correlate with increased Aβ and CACNA1C in the hippocampus and cortex. Moreover, miR-137 prevents tau hyperphosphorylation in Aβ₁₋₄₂-treated SH-SY5Y cells and mice by regulating CACNA1C, highlighting its therapeutic potential in AD.^28,48

Furthermore, the calpain (calpain-1 and calpain-2) becomes hyperactivated in AD due to elevated Ca²⁺, leads to cleavage of p35 into p25, forming the p25/CDK5 complex. This complex promotes tau hyperphosphorylation, amyloid plaques, and exacerbates neurodegeneration. miR-137 regulates calpain-2 by downregulating its expression in PC-12 cells, thereby disrupting the p25/CDK5 pathway and preventing tau pathology and neuronal apoptosis^49,50 Hence, these findings emphasize miR-137's critical role in counteracting AD pathogenesis by modulating calcium dynamics and preventing tau hyperphosphorylation. Its regulation of CACNA1C and calpain-2 underscores its potential as a therapeutic target to reduce neuronal degeneration and improve AD outcomes. Collectively, this evidence highlights the upregulation of miR-137 as a beneficial approach in AD,^23,51 as mentioned in Figure 1.

Effects of miR-137 and tau protein editing

Abnormal splicing of Tau mRNA generates six isoforms (Tau1-Tau6) with varying 3R/4R sequences, essential for microtubule stability. In AD, hyperphosphorylated Tau disrupts microtubules, forming neurofibrillary tangles that drive neuronal death and synaptic loss.^52,53 It has been investigated that, miR-137 enriched in the cortex, regulates synapses and neurons. Its downregulation increases glycogen synthase kinase 3 beta (GSK-3β), disrupting tau phosphorylation in AD.⁵⁴ Moreover, abnormal splicing of microtubule-associated protein tau (MAPT), especially in exon 10, disrupts the 1:1 ratio of 3R/4R Tau isoforms. This imbalance contributes to neurodegenerative diseases like AD, affecting microtubule stability and neuronal health.^55,56 Notably, miR-137 has been shown to influence this splicing process in tauopathies especially in progressive supranuclear palsy (PSP) and modulate the 3R/4R ratio in neurons,⁵⁵ suggesting therapeutic potential in AD; however, direct confirmation in AD models remains necessary.

miR-137 modulates sleep-wake rhythms

Circadian rhythms are vital for brain health, with disruptions often linked to neurodegenerative diseases like AD. miR-137 modulates sleep-wake cycles via hypocretin signaling, essential for stability and wakefulness, while its downregulation enhances arousal and impacts neuroplasticity.⁵⁷ Moreover, exercise enhances cognitive function by promoting memory and neurogenesis via miR-137 in aging mice. Declining neurogenesis with age implicates 5-hydroxymethylcytosine in miR-137 regulation, suggesting epigenetic interventions as potential strategies against aging and neurodegenerative diseases like AD.⁵⁸ Moreover, miR-137 regulates circadian rhythms by directly targeting core clock genes CLOCK and BMAL1, which drive daily oscillations in neurons. Overexpression of miR-137 suppresses these genes, fine-tuning circadian gene expression and reducing oxidative stress linked to clock dysfunction, as reported in hippocampal neurons.^59,60 Conversely, miR-137 deficiency destabilizes circadian cycles, impairing sleep-wake regulation and metabolic homeostasis. This positions miR-137 as a critical modulator of circadian alignment, with implications for brain health.

Circadian disruption and AD exacerbate one another: impaired sleep disrupts glymphatic Aβ clearance, while Aβ accumulation damages circadian pacemaker neurons in the suprachiasmatic nucleus.⁶¹ miR-137 lies at this intersection, as AD-related stressors suppress miR-137,³⁴ further dysregulating circadian genes and worsening sleep. This creates a feedback loop as miR-137 downregulation amplifies neuronal vulnerability in regions like the hippocampus,⁵¹ accelerating both circadian misalignment and AD progression. Restoring miR-137 could break this cycle, offering dual therapeutic benefits.

miR-137 in signaling therapy. Furthermore, miR-137 regulates NMDARs and AMPARs, counteracting Aβ-induced synaptic degeneration by inhibiting AMPAR endocytosis and promoting mGluR-dependent Long-Term Depression. It modulates GABA receptors, affecting long term potentiation (LTP) and synaptic signaling. Targeting genes like GSK-3β, MAPK1, and MAPK3, miR-137 preserves synaptic integrity.^62,63 Hence, glutamatergic, GABAergic, and neuroprotective kinase signaling pathways are important for synaptic plasticity and memory formation, further highlighting miR-137's potential as a therapeutic target in AD.

miR-137 in neuronal stem cell growth, differentiation, and apoptosis

Repairing damaged neurons through directed stem cell differentiation shows potential in AD by replacing lost or dysfunctional neural cells.⁶⁴ Preclinical studies demonstrate that induced pluripotent stem cells can differentiate into functional neurons, improving cognitive deficits in AD animal models.^65,66 However, challenges like integration into existing neural circuits and long-term safety remain.⁶⁷ Clinical trials are ongoing to assess translational feasibility. In recent years, the role of miR-137, in neuronal stem cells (NSCs) growth, differentiation, and apoptosis has gained significant attention.^51,68 miR-137 is crucial not only in regulating of the proliferation and differentiation of NSCs but also in determining their survival, making it a key player in neuroplasticity and the maintenance of neuronal function key factors of AD. miR-137, highly expressed in the dentate gyrus, promotes neuronal differentiation by targeting RTVP-1 and CXCR4, maintaining neurogenesis and brain plasticity, especially during aging.^69,70 Moreover, miR-137 regulates NSC differentiation and cortical neuron migration during brain development via the TLX-LSD1 pathway.⁷¹ These findings suggest that miR-137 plays a significant role in early brain development. Additionally, miR-137 balances adult NSC proliferation and differentiation via Sox2 and MeCP2 regulation.⁷² A high-fat diet lowers miR-137 by increasing MeCP2, linking diet to impaired neurogenesis and AD risk.^68,72 This finding has important implications for lifestyle interventions that might influence the progression of neurodegenerative disease like AD.

miR-137 and synaptic function

miR-137 is crucial for synaptic plasticity, essential for learning and memory. Dysregulation impairs hippocampal synaptic function, causing cognitive deficits.⁷³ It regulates synaptic function by targeting presynaptic proteins (Syt1, complexin-1, synapsin-3) critical for vesicle fusion and synapse formation. Through these targets, it modulates vesicle availability and neurotransmitter release, shaping LTP. Overexpression depletes vesicle pools, disrupting dentate gyrus, LTP and impairing memory, while inhibition enhances vesicle accumulation and synaptic strength, rescuing LTP deficits suggesting tight homeostatic control. In tauopathies like PSP/AD, where these presynaptic proteins may be dysregulated, miR-137 manipulation could offer therapeutic leverage.^15,74,75 These roles highlight its therapeutic potential for treating cognitive deficits in disorders like AD, schizophrenia, and epilepsy, where synaptic plasticity is disrupted. Further research is essential to uncover its full potential.

miR-137 regulates genes essential for neurogenesis, apoptosis, and synaptic signaling, including CDK6, TGFβ2, and c-KIT.^76,77 Moreover, miR-137 also targets key transcription factors involved in stem cell self-renewal, including Klf4 and Tbx3.⁷⁸ It promotes NSC differentiation and targets KREMEN1, a Wnt pathway protein linked to neuronal apoptosis and synapse loss in AD. Additionally, SNHG1 acts as a competing endogenous RNA (ceRNA) that inhibits miR-137 activity. Knockdown of SNHG1 restores miR-137 function, allowing it to suppress KREMEN1 expression, thereby protecting neurons from Aβ-induced damage and highlighting miR-137's neuroprotective role in AD,⁷⁹ overall, therapeutic role by targeting KEGG pathways are summarize in Figure 2.

Figure 2.

KEGG pathways, summary of miR-137 with therapeutic potential in AD. This figure highlights the protective roles of miR-137 in AD by targeting key pathways. miR-137 reduces Aβ accumulation, neuroinflammation, and tau hyperphosphorylation while promoting synaptic health, memory, and plasticity (MAPK/ERK and Wnt pathways). It also enhances mitochondrial biogenesis (oxidative phosphorylation), regulates calcium signaling to prevent excitotoxicity, and supports NMDA receptor signaling for synaptic activity. These combined actions position miR-137 as a promising therapeutic target for AD.

Biomarker and therapeutic potential of miR-137 in AD

AD diagnosis relies on neuroimaging and cognitive tests, with no reliable serological markers available. Recent studies show consistent downregulation of miR-137 in AD brains and biofluids, linking it to synaptic dysfunction, Aβ accumulation, and tau hyperphosphorylation.^29,43,80 Given its role in neuronal function and AD-related pathways, miR-137 holds promise as a diagnostic biomarker and therapeutic target. Currently, miR-137 partially fulfills these criteria, but large-scale longitudinal studies are lacking. Further research must standardize detection methods and validate findings in diverse populations. But, for the translational applicability of miR-137 as a biomarker is constrained by limited clinical studies and inconsistent results across cohorts. Hence, for miR-137 to be considered a reliable AD biomarker, it must meet key criteria, including: specificity (distinguishing AD from other neurodegenerative diseases), sensitivity (detecting early-stage AD or preclinical pathology), reproducibility (consistent dysregulation across independent cohorts and biofluids), and mechanistic relevance (association with AD pathogenesis).

miR-137 as a therapeutic target

miR-137 regulates key AD-related pathways, including Aβ production, tau phosphorylation, and neuroinflammation. Its restoration in preclinical models reduces Aβ levels and improves cognition, highlighting its potential as a therapeutic candidate pending further clinical validation.²⁹ Moreover, In AD disease models, miR-137 has been shown to reduce Aβ plaque accumulation and enhance cognitive performance. It achieves this by modulating key molecular pathways involved in synaptic function and neuronal survival, suggesting its potential as a therapeutic candidate.^81–83 miR-137 exhibits neuroprotective properties across various brain injury in-vitro models. In an in-vitro ischemic stroke model, it regulates the Notch signaling pathway, mitigating oxidative stress, inflammation, and neuronal injury.⁸⁴ In traumatic brain injury, early administration of miR-137 mimics reduces glial scar formation and enhances neuronal survival, promoting recovery and locomotor improvement in a mouse model.⁸⁵ This indicates the potential of miR-137 in enhancing recovery following brain injuries. Moreover, another animal study highlighted its involvement in regulating mitophagy and cellular stress responses, further supporting its potential for neuroprotection and disease modulation.⁸⁶ As several genetic pathways have been implicated in AD, and miR-137 is known to modulate multiple genes involved in its pathogenesis. To identify the most promising target genes for AD management, we conducted computational prediction analyses, as discussed below.

Computational prediction analysis of miR-137's role in AD

Interestingly, miR-137 modulates the expression of over 1000 predicted target genes,^18,68 influencing cellular proliferation, differentiation, and synaptic function. This broad regulatory scope underscores the importance of understanding the miR-137-associated pathways in the context of neuronal health and diseases.^55,87,88 The role of miR-137 in AD can be understood through genetic associations and its involvement in molecular pathways that influence neurodegeneration. Prediction analyses through bioinformatics integrate these aspects to determine its regulatory impact and therapeutic potential. Hence, for the prediction analyses, we extensively searched different databases and critically reviewed recent studies up to December 2024, specifically focused on miR-137 and its connection to AD.

We explored miRDB (https://mirdb.org) and identified target genes (1217) for miR-137. For AD-related genes, GeneCards (https://www.genecards.org/), OMIM (https://www.omim.org/), and String (https://string-db.org/) revealed key genes (924) associated with AD pathogenesis, these databases providing valuable insights into the interplay between miR-137 and AD-related molecular pathways. Our analysis revealed significant overlaps in the genetic targets and molecular pathways influenced by miR-137, shedding light on its multifaceted role in AD pathogenesis. The overlap of miR-137-regulated genes with AD-associated genes shown in the Venn diagram (Figure 3A), highlights miR-137 modulates key molecular hubs driving AD progression. The overlapping region contains 37 common genes, which may represent key molecular links between miR-137 and AD pathophysiology. These overlapping genes subjected to further network and pathway analyses to identify potential mechanisms through which miR-137 may influence AD-related biological processes, offering insight into miR-137's therapeutic and regulatory roles in neurodegeneration. Additionally, Ingenuity Pathway Analysis (IPA) network analyses performed on all the overlapping genes using STRING (https://string-db.org/), IPA can predicts key regulators, identifies disrupted pathways, and links data to biological processes, aiding hypothesis generation and target discovery. IPA network analysis of 37 overlapping genes shown in Figure 3B. Moreover, pathway enrichment analyses revealed that most of the genes are involved in the AD pathogenesis like memory, learning, synaptic plasticity, and cell development as shown in Figure 3C.

Figure 3.

Prediction analysis of genes and signal pathways. (a) The Venn diagram shows 37 overlapping genes between miR-137-regulated (1217) and AD-associated (924) genes, suggesting shared roles in pathways like inflammation, oxidative stress, and synaptic plasticity. (b) IPA network of 37 shared genes which can be focused as a therapeutic targets for AD, and C: GO analyses shows genes are involved in the AD pathogenesis like memory, learning, synaptic plasticity, neurogenesis, and cell development, x-axis (signal intensity) and y-axis (gene functions).

This analysis helps prioritize pathways for further investigation based on their relevance and contribution to the studied conditions. Hence, targeting these 37 genes, miR-137 may mitigate different AD associated pathways, providing potential therapeutic insights into AD. Furthermore, Table 3 presents a comprehensive overview of 37 genes implicated in AD pathogenesis. Further investigation into miR-137's regulatory influence on these targets may uncover novel therapeutic avenues for the treatment and management of AD.

Table 3.

Computational prediction of 37 AD-related genes potentially regulated by miR-137.

Genes	Roles in AD (cell, pre-clinical and clinical investigations)	References
NPC1	NPC1 mutations impair cholesterol transport, leading to protein aggregation, cytotoxicity, and potentially contributing to AD pathology.	⁸⁹
TARDBP	TDP-43 regulates RNA and gene expression; its pathology appears in ∼57% of AD cases, linking it to worse cognitive decline and broader neurodegeneration.	^90,91
SYNJ1	SYNJ1 regulates synaptic vesicle recycling; its increase links to Aβ toxicity in AD, while lower levels offer protection.	^92,93
EGR2	AD involves amyloid and tau pathology, with early myelin damage. EGR2, linked to inflammation and neuroprotection, may serve as a biomarker and therapeutic target.	^94,95
PIK3CA	Microglia and the PI3K-AKT-mTOR pathway are key in AD. PIK3CA links to Aβ response, apoptosis, insulin signaling, and glucose metabolism in AD.	^96,97
NOTCH1	NOTCH1 affects AD via gamma-secretase, influencing Aβ production, immune responses, and m6A methylation through links with FTO.	^98,99
GSK3β	GSK3B promotes tau and Aβ pathology in AD, affects autophagy and neuron survival, and is a potential therapeutic target.	¹⁰⁰
BACE2	BACE2 reduces Aβ42 production and neuronal death, making it a potential Alzheimer's therapy target.	¹⁰¹
IDE	IDE degrades Aβ; its activation may help treat AD.	^102,103
PTGS2	PTGS2 is linked to AD via ferroptosis and inflammation; salidroside and quercetin may offer protection.	^104,105
NOX4	NOX4 drives oxidative stress and ferroptosis in AD; dioscin may counteract this by downregulating NOX4.	^106,107
ATG14	ATG14 regulates autophagy; its dysfunction worsens neurodegeneration in AD.	^108,109
PIK3R3	PIK3R3 is linked to Aβ plaque formation and gene changes in AD brains.	¹¹⁰
WNT5A	WNT5A protects synapses from Aβ but can also trigger JNK-mediated loss, contributing to AD.	¹¹¹
WNT7A	Reduced WNT7A and increased Wnt inhibitors impair synapses and may raise AD risk.	^112,113
GRM5	GRM5 modulates AD risk via calcium signaling and Aβ-prion protein interactions.	^114,115
GRIN2A	GRIN2A dysfunction impairs NMDA signaling in epilepsy and AD.	¹¹⁶
ITPR3	ITPR3 modulates AD via calcium signaling and synaptic dysfunction.	¹¹⁷
IRS2	IRS2 modulates both insulin pathways and amyloid-beta in AD, suggesting dual roles in cognitive decline and neuroprotection.	¹¹⁸
RYR3	RYR3 affects calcium signaling; its dysfunction in AD may drive neurodegeneration and hyperactivity.	^119,120
PLCB1	PLCB1 is upregulated in AD, causing calcium overload and Aβ-linked neurotoxicity.	¹²¹
CAPN2	CAPN2 cleaves tau in AD; its inhibition may reduce tau aggregation and neurodegeneration.	¹²²
ULK2	ULK2 mediates mitophagy and synaptic loss in AD; its inhibition may reduce Aβ-induced damage.	¹²³
CACNA1C	CACNA1C disrupts calcium balance in AD; its inhibition may ease Aβ-induced neuronal damage.	^28,124
WNT16	WNT16 is altered in AD; its activation may protect neurons from Aβ-induced damage.	¹²⁵
FZD3	FZD3 is altered in AD; its activation may reduce Aβ-induced stress and synaptic damage.	^126,127
HOXD10	Inhibiting miR-10b-5p slowed AD progression by upregulating HOXD10 and blocking Rho/ROCK signaling, offering potential therapeutic insights.	¹²⁸
SAR1B	SAR1B, tied to lipid metabolism and Aβ generation, is linked to CMRD; its role in dementia remains unexplored	^129,130
HLA-DQA1	HLA-DQA1, an immune-related gene, is linked to AD risk and cognitive decline, and identified as a potential genetic marker.	¹³¹
HLA-DQB1	HLA-DQB1 variants are linked to reduced tau pathology, delayed AD onset, and serve as potential genetic markers.	¹³²
CASP3	CASP3 drives apoptosis, linked to autophagy loss, mitochondrial stress, and DNA damage, however, to validate the role of CASP3 in AD, experimental investigations are needed.	¹³³
SLC25A5	A study compares plasma peptides in AD patients vs. controls and other diseases to identify AD-specific proteins, hence, further experimental investigations are necessary.	¹³⁴
MAPK8	MAPK8/JNK1 regulates Aβ, tau, and neuroinflammation in AD by network pharmacology analyses, but wet lab experiments are required for validation.	¹³⁵
BRAF	BRAF influences inflammation, apoptosis, and synaptic issues, with sex-specific roles, however, to validate the role of BRAF in AD, further experiments are required.	¹³⁶
CACNA1D	CACNA1D alters calcium signaling in AD; its inhibition may reduce Aβ-induced neurodegeneration, however, further investigations are needed.	¹³⁷
COPA	COPA has been studied in zebrafish and appears to play a role in Notch signaling during central nervous system development; however, in vivo and in vitro studies are necessary to confirm its involvement in AD	¹³⁸
HTT	Mutant HTT contributes to neurodegeneration in AD through interaction with FKBP5, identified as a potential therapeutic target, though further experimental validation is needed.	¹³⁹

These findings establish miR-137 as a pivotal regulator of genes and pathways implicated in AD. Targeting miR-137 and its pathways holds therapeutic potential against AD. Future research could explore these pathways for developing miRNA-based interventions for AD. Hence, bioinformatics tools and databases have been pivotal in uncovering the role of miR-137 in AD. Several resources have been employed to analyze miR-137's genetic targets, pathway involvements, and expression profiles, aiding in the understanding of its role.¹⁴⁰ Databases like miRBase, miRDB, and miRTarBase provide detailed annotations of miR-137 sequences, predicted target genes, and its expression dynamics across different conditions, including neurodegenerative diseases like AD. These tools help researchers identify key genes and pathways regulated by miR-137, such as GRIN2A, CACNA1C, and GSK-3β, which are critical in synaptic plasticity, amyloid metabolism, and tau phosphorylation. By integrating machine learning tools for network analysis, these databases facilitate the prediction of miR-137's broader role in neurodegeneration, enabling visualization and modeling of miR-137-associated pathways, further highlighting its potential as both a biomarker and therapeutic target in AD.

Conclusion and future perspectives

In summary, miR-137 has emerged as a promising biomarker for AD due to its involvement in key molecular pathways associated with neurodegeneration, as well as its reduced expression in the serum of AD patients. Its non-invasive nature makes it an attractive candidate for early diagnosis, which is crucial for timely intervention and improved patient outcomes. Moreover, miR-137's regulatory role in tau phosphorylation, neuronal differentiation, neuroinflammation, and synaptic plasticity makes it a valuable target for both diagnostic and therapeutic strategies in AD as revealed by our prediction analyses as well. The advancement of reliable biomarkers such as miR-137 has the potential to greatly enhance early detection of AD, improve tracking of its progression, and pave the way for more effective treatments. Ongoing research on miRNA-based diagnostics and therapies highlights miR-137 as a promising tool to revolutionize the diagnosis and treatment of AD in the future.

Footnotes

Acknowledgements

The authors have no acknowledgments to report.

ORCID iDs

Muhammad Wasim

Junhao Guo

Zhendong Wang

Rabia Parveen

Yajun Wang

Guoda Ma

Author contributions

Muhammad Wasim: Data curation; Methodology; Software; Writing – original draft; Writing – review & editing.

Junhao Guo: Data curation; Formal analysis; Investigation; Software; Validation; Writing – review & editing.

Zhendong Wang: Conceptualization; Formal analysis; Project administration; Visualization; Writing – review & editing.

Rabia Parveen: Formal analysis; Methodology; Software; Writing – review & editing.

Riling Chen: Formal analysis; Investigation; Validation; Writing – review & editing.

Yajun Wang: Conceptualization; Formal analysis; Investigation; Project administration; Supervision; Writing – review & editing.

Guoda Ma: Conceptualization; Formal analysis; Investigation; Project administration; Supervision; Visualization; Writing – review & editing.

Funding

Support for this work includes funding from the National Natural Science Foundation of China (81670252, 81770034), Guangdong Basic and Applied Basic Foundation (2019A1515011306), and a postdoctoral start-up fund from Shunde Women and Children's Hospital, Guangdong Medical University, China (2024BSHQD002).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Querfurth

LaFerla

. Alzheimer's disease. N Engl J Med 2010; 362: 329–344.

Wang

Geng

. Alzheimer's disease hypothesis and related therapies. Transl Neurodegener 2018; 7: 2.

Tam

Dosso

Robillard

. The impact of a global pandemic on people living with dementia and their care partners: analysis of 417 lived experience reports. J Alzheimers Dis 2021; 80: 865–875.

Jia

Wei

Chen

, et al. The cost of Alzheimer's disease in China and re-estimation of costs worldwide. Alzheimers Dement 2018; 14: 483–491.

Chan

Wang

, et al. Epidemiology of Alzheimer's disease and other forms of dementia in China, 1990-2010: a systematic review and analysis. Lancet 2013; 381: 2016–2023.

Jia

Ning

Chen

, et al. Biomarker changes during 20 years preceding Alzheimer’s disease. N Engl J Med 2024; 390: 712–722.

Zheng

Wang

. Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy. Protein Cell 2025; 16: 83–120.

Zhang

Wang

, et al. Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies. Signal Transduct Target Ther 2024; 9: 11.

Hébert

Horré

Nicolaï

, et al. MicroRNA regulation of Alzheimer's amyloid precursor protein expression. Neurobiol Dis 2009; 33: 422–428.

10.

Long

Lahiri

. MicroRNA-101 downregulates Alzheimer's amyloid-β precursor protein levels in human cell cultures and is differentially expressed. Biochem Biophys Res Commun 2011; 404: 889–895.

11.

Guévremont

Tsui

Knight

, et al. Plasma microRNA vary in association with the progression of Alzheimer's disease. Alzheimers Dement (Amst) 2022; 14: e12251.

12.

Hoss

Labadorf

Beach

, et al. microRNA profiles in Parkinson's disease prefrontal cortex. Front Aging Neurosci 2016; 8: 36.

13.

Guo

Yang

Jiang

, et al. MicroRNA editing patterns in Huntington’s disease. Sci Rep 2022; 12: 3173.

14.

Ramirez-Gomez

Dalal

Devara

, et al. MicroRNA-based recent research developments in Alzheimer's disease. J Alzheimers Dis 2025; 104: 14–31.

15.

Siegert

Seo

Kwon

, et al. The schizophrenia risk gene product miR-137 alters presynaptic plasticity. Nat Neurosci 2015; 18: 1008–1016.

16.

Khoodoruth

MAS

Khoodoruth

WNC

Uroos

, et al. Diagnostic and mechanistic roles of MicroRNAs in neurodevelopmental & neurodegenerative disorders. Neurobiol Dis 2024; 202: 106717.

17.

Lagos-Quintana

Rauhut

Yalcin

, et al. Identification of tissue-specific microRNAs from mouse. Curr Biol 2002; 12: 735–739.

18.

Wang

Chen

Zhou

, et al. miR-137: a novel therapeutic target for human glioma. Mol Ther Nucleic Acids 2020; 21: 614–622.

19.

Yin

Lin

Luo

, et al. miR-137: a new player in schizophrenia. Int J Mol Sci 2014; 15: 3262–3271.

20.

Geekiyanage

Chan

. MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid beta, novel targets in sporadic Alzheimer's disease. J Neurosci 2011; 31: 14820–14830.

21.

Geekiyanage

Upadhye

Chan

. Inhibition of serine palmitoyltransferase reduces abeta and tau hyperphosphorylation in a murine model: a safe therapeutic strategy for Alzheimer's disease. Neurobiol Aging 2013; 34: 2037–2051.

22.

Geekiyanage

Jicha

Nelson

, et al. Blood serum miRNA: non-invasive biomarkers for Alzheimer's disease. Exp Neurol 2012; 235: 491–496.

23.

Huang

Zhang

Zheng

, et al. Upregulation of miR-137 protects anesthesia-induced hippocampal neurodegeneration. Int J Clin Exp Pathol 2014; 7: 5000–5007.

24.

Improta-Caria

Nonaka

CKV

Cavalcante

BRR

, et al. Modulation of MicroRNAs as a potential molecular mechanism involved in the beneficial actions of physical exercise in Alzheimer disease. Int J Mol Sci 2020; 21: 4977.

25.

Di Liegro

Schiera

Proia

, et al. Physical activity and brain health. Genes (Basel) 2019; 10: 20.

26.

Jin

Wang

, et al. Epigenetic axis of SNHG19/miR-137/TNFAIP1 modulates amyloid beta peptide 25–35-induced SH-SY5Y cytotoxicity. Epigenomics 2022; 14: 187–198.

27.

Hosseininia

Rostami

Delphi

, et al. Memory impairment was ameliorated by corticolimbic microinjections of arachidonylcyclopropylamide (ACPA) and miRNA-regulated lentiviral particles in a streptozotocin-induced Alzheimer's rat model. Exp Neurol 2023; 370: 114560.

28.

Jiang

Chen

, et al. Micro-RNA-137 inhibits tau hyperphosphorylation in Alzheimer’s disease and targets the CACNA1C gene in transgenic mice and human neuroblastoma SH-SY5Y cells. Med Sci Monit 2018; 24: 5635–5644.

29.

Jiang

Bian

Chen

, et al. miRNA-137-5p improves spatial memory and cognition in Alzheimer's mice by targeting ubiquitin-specific peptidase 30. Animal Model Exp Med 2023; 6: 526–536.

30.

Dai

Han

, et al. MiR-137 attenuates spinal cord injury by modulating NEUROD4 through reducing inflammation and oxidative stress. Eur Rev Med Pharmacol Sci 2018; 22: 1884–1890.

31.

Rahaie

Noroozi

. A nanobiosensor based on graphene oxide and DNA binding dye for multi-microRNAs detection. Biosci Rep 2019; 39: BSR20181404.

32.

Yang

Kang

Lin

, et al. Up-regulation of miR-137 can inhibit PTN in target manner to regulate PTN/PTPRZ pathway to prevent cognitive dysfunction caused by propofol. Am J Transl Res 2020; 12: 7490–7500.

33.

Mao

Liu

, et al. Nuclear microRNA-mediated transcriptional control determines adult microglial homeostasis and brain function. Cell Rep 2024; 43: 113964.

34.

Tan

Zhang

. miR-137 attenuates Aβ-induced neurotoxicity through inactivation of NF-κB pathway by targeting TNFAIP1 in Neuro2a cells. Biochem Biophys Res Commun 2017; 490: 941–947.

35.

Azimzadeh

Nasirizadeh

Rahaie

, et al. Early detection of Alzheimer's disease using a biosensor based on electrochemically-reduced graphene oxide and gold nanowires for the quantification of serum microRNA-137. RSC Adv 2017; 7: 55709–55719.

36.

Jazvinscak Jembrek

Hof

Simic

. Ceramides in Alzheimer's disease: key mediators of neuronal apoptosis induced by oxidative stress and abeta accumulation. Oxid Med Cell Longev 2015; 2015: 346783.

37.

Puglielli

. Two endoplasmic reticulum (ER)/ER Golgi intermediate compartment-based lysine acetyltransferases post-translationally regulate BACE1 levels. J Biol Chem 2009; 284: 2482–2492.

38.

Chaubey

Patel

Rastogi

, et al. Therapeutic potential of cyanobacterial pigment protein phycoerythrin: in silico and in vitro study of BACE1 interaction and in vivo Abeta reduction. Int J Biol Macromol 2019; 134: 368–378.

39.

Han

Holtzman

McKeel

Jr , et al. Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer's disease: potential role in disease pathogenesis. J Neurochem 2002; 82: 809–818.

40.

Huang

, et al. Deregulation of sphingolipid metabolism in Alzheimer's disease. Neurobiol Aging 2010; 31: 398–408.

41.

Czubowicz

Strosznajder

. Ceramide in the molecular mechanisms of neuronal cell death. The role of Sphingosine-1-Phosphate. Mol Neurobiol 2014; 50: 26–37.

42.

Cordy

Hussain

Dingwall

, et al. Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein. Proc Natl Acad Sci U S A 2003; 100: 11735–11740.

43.

Nong

Wei

, et al. miR-137 overexpression protects neurons from Aβ-induced neurotoxicity via ERK1/2. All Life 2021; 14: 522–529.

44.

Davare

Avdonin

Hall

, et al. A beta2 adrenergic receptor signaling complex assembled with the Ca2 + channel Cav1.2. Science 2001; 293: 98–101.

45.

Davare

Hell

. Increased phosphorylation of the neuronal L-type Ca(2+) channel Ca(v)1.2 during aging. Proc Natl Acad Sci U S A 2003; 100: 16018–16023.

46.

Jakobsson

Palsson

Sellgren

, et al. CACNA1C Polymorphism and altered phosphorylation of tau in bipolar disorder. Br J Psychiatry 2016; 208: 195–196.

47.

Anekonda

Quinn

Harris

, et al. L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer's disease. Neurobiol Dis 2011; 41: 62–70.

48.

Furukawa

Wang

Yao

, et al. Alteration in calcium channel properties is responsible for the neurotoxic action of a familial frontotemporal dementia tau mutation. J Neurochem 2003; 87: 427–436.

49.

Tang

, et al. MicroRNA-137-3p protects PC12 cells against oxidative stress by downregulation of Calpain-2 and nNOS. Cell Mol Neurobiol 2021; 41: 1373–1387.

50.

Tang

Ling

, et al. MiR-137-3p rescue motoneuron death by targeting calpain-2. Nitric Oxide 2018; 74: 74–85.

51.

Bodai

Borosta

Ferencz

, et al. The role of miR-137 in neurodegenerative disorders. Int J Mol Sci 2024; 25: 7229.

52.

Leszek

Malyszczak

Janicka

, et al. Total tau in cerebrospinal fluid differentiates Alzheimer's disease from vascular dementia. Med Sci Monit 2003; 9: CR484–CR488.

53.

Medina

Avila

. New perspectives on the role of tau in Alzheimer's disease. Implications for therapy. Biochem Pharmacol 2014; 88: 540–547.

54.

Zhou

Huangfu

Yang

, et al. MiR-137-3p mechanisms of action and blood-brain barrier penetrating and neuron-targeting lipid nanoparticles deliver miR-137-3p for the treatment of Alzheimer's disease. J Drug Deliv Sci Technol 2024; 100: 106100.

55.

Smith

Delay

Girard

, et al. MicroRNA-132 loss is associated with tau exon 10 inclusion in progressive supranuclear palsy. Hum Mol Genet 2011; 20: 4016–4024.

56.

Caffrey

Joachim

Paracchini

, et al. Haplotype-specific expression of exon 10 at the human MAPT locus. Hum Mol Genet 2006; 15: 3529–3537.

57.

Holm

Possovre

Bandarabadi

, et al. The evolutionarily conserved miRNA-137 targets the neuropeptide hypocretin/orexin and modulates the wake to sleep ratio. Proc Natl Acad Sci U S A 2022; 119: e2112225119.

58.

Jessop

Toledo-Rodriguez

. Hippocampal TET1 and TET2 expression and DNA hydroxymethylation are affected by physical exercise in aged mice. Front Cell Dev Biol 2018; 6: 45.

59.

Zhang

Yang

, et al. Co-regulation of circadian clock genes and microRNAs in bone metabolism. J Zhejiang Univ Sci B 2022; 23: 529–546.

60.

Kim

Lee

. The role of microRNAs in the molecular link between circadian rhythm and autism spectrum disorder. Anim Cells Syst (Seoul) 2023; 27: 38–52.

61.

Khandayataray

Murthy

. Exploring the nexus: sleep disorders, circadian dysregulation, and Alzheimer’s disease. Neuroscience 2025; 574: 21–41.

62.

Wright

Turner

Calhoun

, et al. Potential impact of miR-137 and its targets in schizophrenia. Front Genet 2013; 4: 58.

63.

Olde Loohuis

Stoerchel

, et al. MicroRNA-137 controls AMPA-receptor-mediated transmission and mGluR-dependent LTD. Cell Rep 2015; 11: 1876–1884.

64.

Lee

Kim

Lee

, et al. Mitochondrial genome mutations and neuronal dysfunction of induced pluripotent stem cells derived from patients with Alzheimer's disease. Cell Prolif 2022; 55: e13274.

65.

Flannagan

Stopperan

Hauger

, et al. Cell type and sex specific mitochondrial phenotypes in iPSC derived models of Alzheimer's disease. Front Mol Neurosci 2023; 16: 1201015.

66.

Penney

Ralvenius

Tsai

. Modeling Alzheimer’s disease with iPSC-derived brain cells. Mol Psychiatry 2020; 25: 148–167.

67.

Rahimi Darehbagh

Seyedoshohadaei

Ramezani

, et al. Stem cell therapies for neurological disorders: current progress, challenges, and future perspectives. Eur J Med Res 2024; 29: 86.

68.

Mahmoudi

Cairns

. MiR-137: an important player in neural development and neoplastic transformation. Mol Psychiatry 2017; 22: 44–55.

69.

Smrt

Szulwach

Pfeiffer

, et al. MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells 2010; 28: 1060–1070.

70.

Silber

Lim

Petritsch

, et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 2008; 6: 14.

71.

Sun

Murai

, et al. miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells. Nat Commun 2011; 2: 29.

72.

Szulwach

Smrt

, et al. Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J Cell Biol 2010; 189: 127–141.

73.

Wang

Tsai

. MicroRNAs in learning and memory and their impact on Alzheimer's disease. Biomedicines 2022; 10: 1856.

74.

Thomas

Gross

Bassell

. microRNAs sculpt neuronal communication in a tight balance that is lost in neurological disease. Front Mol Neurosci 2018; 11: 55.

75.

Zhang

Liao

Wen

, et al. Synaptic plasticity in schizophrenia pathophysiology. IBRO Neurosci Rep 2022; 13: 478–487.

76.

Tamim

Uren

, et al. Genomic analyses reveal broad impact of miR-137 on genes associated with malignant transformation and neuronal differentiation in glioblastoma cells. PLoS One 2014; 9: e85591.

77.

Lim

Lau

Garrett-Engele

, et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 2005; 433: 769–773.

78.

Jiang

Ren

Nair

. MicroRNA-137 represses Klf4 and Tbx3 during differentiation of mouse embryonic stem cells. Stem Cell Res 2013; 11: 1299–1313.

79.

Wang

Chen

. Knockdown of lncRNA SNHG1 attenuated Abeta25-35-inudced neuronal injury via regulating KREMEN1 by acting as a ceRNA of miR-137 in neuronal cells. Biochem Biophys Res Commun 2019; 518: 438–444.

80.

Gentile

Morello

La Cognata

, et al. Dysregulated miRNAs as biomarkers and therapeutical targets in neurodegenerative diseases. J Pers Med 2022; 12: 70.

81.

Abuelezz

Nasr

AbdulKader

, et al. MicroRNAs as potential orchestrators of Alzheimer's disease-related pathologies: insights on current status and future possibilities. Front Aging Neurosci 2021; 13: 743573.

82.

Palumbo

Gautam

Sonneborn

, et al. MicroRNA137-loaded lipid nanoparticles regulate synaptic proteins in the prefrontal cortex. Mol Ther 2023; 31: 2975–2990.

83.

Donohoe

Cosgrove

Motherills

, et al. Genetic risk variants interacting with MIR137: effects on cognition, brain structure and brain function in patients and healthy participants. Eur Neuropsychopharmacol 2019; 29: S729–SS30.

84.

Shi

Dong

, et al. MicroRNA-137 protects neurons against ischemia/reperfusion injury through regulation of the Notch signaling pathway. Exp Cell Res 2017; 352: 1–8.

85.

Liu

Teng

. Early-stage application of Agomir-137 promotes locomotor recovery in a mouse model of motor cortex injury. Int J Mol Sci 2023; 24: 17156.

86.

Zhang

Zhuang

, et al. MicroRNA-137 is a novel hypoxia-responsive MicroRNA that inhibits mitophagy via regulation of two mitophagy receptors FUNDC1 and NIX. J Biol Chem 2014; 289: 10691–10701.

87.

Cheng

Wang

Tan

, et al. Partial loss of psychiatric risk gene Mir137 in mice causes repetitive behavior and impairs sociability and learning via increased Pde10a. Nat Neurosci 2018; 21: 1689–1703.

88.

Verma

Augustine

Ammar

, et al. A neuroprotective role for microRNA miR-1000 mediated by limiting glutamate excitotoxicity. Nat Neurosci 2015; 18: 379–385.

89.

Lopergolo

Bianchi

Gallus

, et al. Familial Alzheimer's disease associated with heterozygous NPC1 mutation. J Med Genet 2024; 61: 332–339.

90.

Estades Ayuso

Pickles

Todd

, et al. TDP-43-regulated cryptic RNAs accumulate in Alzheimer's disease brains. Mol Neurodegener 2023; 18: 57.

91.

Arseni

Chen

Murzin

, et al. TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP. Nature 2023; 620: 898–903.

92.

Hwang

Jr Dang

Chen

, et al. Triplication of Synaptojanin 1 in Alzheimer's disease pathology in Down Syndrome. Curr Alzheimer Res 2022; 19: 795–807.

93.

Martin

Dowling

Lianekhammy

, et al. Synaptophysin and synaptojanin-1 in Down syndrome are differentially affected by Alzheimer's disease. J Alzheimers Dis 2014; 42: 767–775.

94.

Shi

Lin

, et al. Icariin ameliorates Alzheimer's disease pathology by alleviating myelin injury in 3 × Tg-AD mice. Neurochem Res 2022; 47: 1049–1059.

95.

Pan

Zhao

. Influence of N6-methyladenosine (m6A) modification on cell phenotype in Alzheimer's disease. PLoS One 2023; 18: e0289068.

96.

Wang

Sudan

Peng

, et al. TREM2 Drives microglia response to amyloid-β via SYK-dependent and -independent pathways. Cell 2022; 185: 4153–69.e19.

97.

Wang

Lin

Wang

, et al. TREM2 Ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer's disease mice. Aging (Albany NY) 2020; 12: 20862–20879.

98.

Qiao

Mei

Xia

, et al. The role of m6A modification in the risk prediction and Notch1 pathway of Alzheimer's disease. iScience 2024; 27: 110235.

99.

Miao

Wolfe

. Emerging structures and dynamic mechanisms of γ-secretase for Alzheimer's disease. Neural Regen Res 2025; 20: 174–180.

100.

Thota

Rosato

Dias

, et al. Dietary supplementation with curcumin reduce circulating levels of glycogen synthase kinase-3β and islet amyloid polypeptide in adults with high risk of type 2 diabetes and Alzheimer's disease. Nutrients 2020; 12: 1032.

101.

Schmidt

Hrupka

van Bebber

, et al. The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling. J Clin Invest 2024; 134: e170550.

102.

Hill

Cunningham

. Modelling Alzheimer's disease in a dish: dissecting amyloid-β metabolism in human neurons. Neuronal Signal 2024; 8: NS20230020.

103.

Corraliza-Gomez

Bermejo

Lilue

, et al. Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer's disease and brain aging. J Neuroinflammation 2023; 20: 33.

104.

Yang

Xie

Pei

, et al. Salidroside attenuates neuronal ferroptosis by activating the Nrf2/HO1 signaling pathway in Aβ(1-42)-induced Alzheimer's disease mice and glutamate-injured HT22 cells. Chin Med 2022; 17: 82.

105.

Cao

Liu

, et al. Quercetin inhibits neuronal pyroptosis and ferroptosis by modulating microglial M1/M2 polarization in atherosclerosis. J Agric Food Chem 2024; 72: 12156–12170.

106.

Guan

Mao

Yang

, et al. Dioscin alleviates Alzheimer's disease through regulating RAGE/NOX4 mediated oxidative stress and inflammation. Biomed Pharmacother 2022; 152: 113248.

107.

Park

Cha

Kim

, et al. NOX4 Promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases. Redox Biol 2021; 41: 101947.

108.

Zhang

, et al. Augmenting ATG14 alleviates atherosclerosis and inhibits inflammation via promotion of autophagosome-lysosome fusion in macrophages. Autophagy 2021; 17: 4218–4230.

109.

Tang

Walter

Wohleb

, et al. ATG5 (autophagy related 5) in microglia controls hippocampal neurogenesis in Alzheimer disease. Autophagy 2024; 20: 847–862.

110.

Silver

Janousova

Hua

, et al. Identification of gene pathways implicated in Alzheimer's disease using longitudinal imaging phenotypes with sparse regression. Neuroimage 2012; 63: 1681–1694.

111.

Fang

Pishva

Piers

, et al. Amyloid-β can activate JNK signalling via WNT5A-ROR2 to reduce synapse formation in Alzheimer's disease. J Cell Sci 2025; 138: JCS263526.

112.

Jones

Büchler

Dufor

, et al. A genetic variant of the wnt receptor LRP6 accelerates synapse degeneration during aging and in Alzheimer's disease. Sci Adv 2023; 9: eabo7421.

113.

Curtis

Bakaya

Sharma

, et al. Weighted burden analysis of exome-sequenced late-onset Alzheimer's cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK-3β and WNT signalling pathways. Ann Hum Genet 2020; 84: 291–302.

114.

Sathe

Mangalaparthi

Jain

, et al. Multiplexed phosphoproteomic study of brain in patients with Alzheimer's disease and age-matched cognitively healthy controls. Omics 2020; 24: 216–227.

115.

Haas

Salazar

Kostylev

, et al. Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer's disease. Brain 2016; 139: 526–546.

116.

Wang

Pan

, et al. Identification of early Alzheimer's disease subclass and signature genes based on PANoptosis genes. Front Immunol 2024; 15: 1462003.

117.

Pascual-Caro

Orantos-Aguilera

Sanchez-Lopez

, et al. STIM1 Deficiency leads to specific down-regulation of ITPR3 in SH-SY5Y cells. Int J Mol Sci 2020; 21: 6598.

118.

Ochiai

Sano

Nagayama

, et al. Differential involvement of insulin receptor substrate (IRS)-1 and IRS-2 in brain insulin signaling is associated with the effects on amyloid pathology in a mouse model of Alzheimer's disease. Neurobiol Dis 2021; 159: 105510.

119.

Liu

Cao

, et al. Hippocampal subregion and gene detection in Alzheimer's disease based on genetic clustering random forest. Genes (Basel) 2021; 12: 83.

120.

Gong

Tovar

, et al. Polymorphisms within RYR3 gene are associated with risk and age at onset of hypertension, Diabetes, and Alzheimer's disease. Am J Hypertens 2018; 31: 818–826.

121.

Park

Kim

, et al. Elevation of phospholipase C-β1 expression by amyloid-β facilitates calcium overload in neuronal cells. Brain Res 2022; 1788: 147924.

122.

Cicognola

Satir

Brinkmalm

, et al. Tauopathy-associated tau fragment ending at amino acid 224 is generated by Calpain-2 cleavage. J Alzheimers Dis 2020; 74: 1143–1156.

123.

Lee

Kondapalli

Virga

, et al. Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy. Nat Commun 2022; 13: 4444.

124.

Bocharova

Vagaitseva

Marusin

, et al. Association and gene-gene interactions study of late-onset Alzheimer's disease in the Russian population. Genes (Basel) 2021; 12: 1647.

125.

Aso

Sánchez-Pla

Vegas-Lozano

, et al. Cannabis-based medicine reduces multiple pathological processes in AβPP/PS1 mice. J Alzheimers Dis 2015; 43: 977–991.

126.

Zhang

Fang

Cheng

, et al. Silencing of long noncoding RNA SOX21-AS1 relieves neuronal oxidative stress injury in mice with Alzheimer's disease by upregulating FZD3/5 via the WNT signaling pathway. Mol Neurobiol 2019; 56: 3522–3537.

127.

Zhao

Wang

Mao

, et al. NEAT1 Regulates microtubule stabilization via FZD3/GSK3β/P-tau pathway in SH-SY5Y cells and APP/PS1 mice. Aging (Albany NY) 2020; 12: 23233–23250.

128.

Ruan

, et al. Inhibition of microRNA-10b-5p up-regulates HOXD10 to attenuate Alzheimer's disease in rats via the Rho/ROCK signalling pathway. J Drug Target 2021; 29: 531–540.

129.

Chen

Hsieh

Huang

, et al. Genetic polymorphisms of lipid metabolism gene SAR1 homolog B and the risk of Alzheimer's disease and vascular dementia. J Formos Med Assoc 2016; 115: 38–44.

130.

Okada

Miyashita

Fukuhara

, et al. Anderson's disease/chylomicron retention disease in a Japanese patient with uniparental disomy 7 and a normal SAR1B gene protein coding sequence. Orphanet J Rare Dis 2011; 6: 78.

131.

Zhang

Zou

, et al. Regulation of the late onset Alzheimer's disease associated HLA-DQA1/DRB1 expression. Am J Alzheimers Dis Other Demen 2022; 37: 15333175221085066.

132.

Rosewood

Nho

Risacher

, et al. Genome-wide association analysis across endophenotypes in Alzheimer's disease: main effects and disease stage-specific interactions. Genes (Basel) 2023; 14: 2010.

133.

Baechler

Bloemberg

Quadrilatero

. Mitophagy regulates mitochondrial network signaling, oxidative stress, and apoptosis during myoblast differentiation. Autophagy 2019; 15: 1606–1619.

134.

Florentinus-Mefailoski

Bowden

Scheltens

, et al. The plasma peptides of Alzheimer's disease. Clin Proteomics 2021; 18: 17.

135.

Liu

, et al. Network pharmacology and mechanism studies of the protective effect of ginseng against Alzheimer's disease based on Aβ pathogenesis. Planta Med 2023; 89: 990–1000.

136.

Long

Hauschild

Santinami

, et al. Adjuvant Dabrafenib plus Trametinib in stage III BRAF-mutated melanoma. N Engl J Med 2017; 377: 1813–1823.

137.

Villela

Suemoto

Pasqualucci

, et al.

Do copy number changes in CACNA2D2, CACNA2D3, and CACNA1D constitute a predisposing risk factor for Alzheimer's disease?

Front Genet 2016; 7: 107.

138.

Lim

Moussavi Nik

Ebrahimie

, et al. Analysis of nicastrin gene phylogeny and expression in zebrafish. Dev Genes Evol 2015; 225: 171–178.

139.

Haenig

Atias

Taylor

, et al. Interactome mapping provides a network of neurodegenerative disease proteins and uncovers widespread protein aggregation in affected brains. Cell Rep 2020; 32: 108050.

140.

Elgebaly

Peacock

Christenson

, et al. Integrated bioinformatics analysis confirms the diagnostic value of nourin-dependent miR-137 and miR-106b in unstable angina patients. Int J Mol Sci 2023; 24: 14783.

miR-137: A therapeutic candidate or a key molecular regulator in Alzheimer's disease?

Abstract

Keywords

Introduction

Role and molecular mechanisms of miR-137 in AD

Expression regulation of miR-137 in AD

Inflammatory response mediated by miR-137 in AD

miR-137 delays Aβ protein deposition

miR-137 affects Ca2+ homeostasis and tau hyperphosphorylation

Effects of miR-137 and tau protein editing

miR-137 modulates sleep-wake rhythms

miR-137 in neuronal stem cell growth, differentiation, and apoptosis

miR-137 and synaptic function

Biomarker and therapeutic potential of miR-137 in AD

miR-137 as a therapeutic target

Computational prediction analysis of miR-137's role in AD

Conclusion and future perspectives

Footnotes

Acknowledgements

ORCID iDs

Author contributions

Funding

Declaration of conflicting interests

References

miR-137 affects Ca²⁺ homeostasis and tau hyperphosphorylation