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.

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.