Open access peer-reviewed chapter - ONLINE FIRST

MicroRNAs as Future Treatment Tools and Diagnostic Biomarkers in Alzheimer’s Disease

Written By

Heena Chauhan, Pawan Gupta and Bhagawati Saxena

Submitted: December 7th, 2021Reviewed: February 10th, 2022Published: April 23rd, 2022

DOI: 10.5772/intechopen.103173

Alzheimer's DiseaseEdited by Montasir Elahi

From the Edited Volume

Alzheimer's Disease [Working Title]

Ph.D. Montasir Elahi

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Alzheimer’s disease (AD) is a neurodegenerative disorder and is considered to be the most common form of dementia. This disorder is characterized by the formation of amyloid β (Aβ) plaques, neurofibrillary tangles, and alterations in synaptic function, all of which cause memory loss and behavioral disturbances. Despite the high prevalence of AD, effective therapeutic and diagnostic tools remain unavailable. MicroRNAs (miRNAs, miRs) are regulatory non-coding RNAs that target mRNAs. MiRNAs are involved in the regulation of the expressions of APP and BACE1, Aβ clearance, and the formation of neuro-fibrillary tangles. Furthermore, there are evidences that show alteration in the expression of several miRs in AD. MicroRNA is emerging as a biomarker because they have high specificity and, efficiency, and can be detected in biological fluids such as cerebrospinal fluid, tear, urine, blood. Moreover, miRNAs may be acquired and measured easily by utilizing real-time PCR, next-generation sequencing, or microarray. These techniques are cost-effective in comparison with imaging techniques such as magnetic resonance imaging, positron emission tomography. These features make miRNAs viable therapeutic as well as diagnostic tools in the treatment of AD. This review covers the regulatory function of miRNAs in AD, as well as their prospective applications as diagnostic biomarkers.


  • Alzheimer’s disease
  • dementia
  • pathogenesis
  • microRNAs
  • diagnosis
  • biomarker

1. Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder and is considered to be the most common form of dementia that majorly occurs in aged persons although a familial form of AD can occur in the younger population. Familial (early-onset) AD occurs due to mutations in the amyloid precursor protein (APP), presenilin 1, and presenilin 2 genes [1]. However, further identification of tau gene mutations in familial frontotemporal dementia (FTD) with chromosome 17 has shown a clear relationship between tau malfunction and dementia [2]. These findings show that AD and FTD are related in a hereditary spectrum of degenerative brain illnesses in which tau appears to play a key role [3]. Clinical manifestations of AD include a slow and persistent deterioration in memory, executive functions, and the capacity to carry out daily activities [4, 5]. Dementia affects around 36.5 million individuals worldwide in 2010. Every 20 years, the number of dementia cases is expected to roughly quadruple, reaching 65.7 million in 2030 and 115.4 million in 2050. AD is accounting for the preponderance of these dementia instances, accounting for 60–80% of all dementia cases [6]. Every year, an estimated 5–7 million new instances of AD are diagnosed in the elderly population [7]. In 2020, overall healthcare expenditures for AD treatment are predicted to be $305 billion, with expenditure expected to rise to more than $1 trillion as the population ages [8]. Even moderate developments in preventative and therapeutic techniques that postpone the initiation and advancement of AD can considerably lower the illness’s worldwide impact [9].


2. Pathophysiology involved in AD

The scientific field dedicated for understanding the mechanisms involved in the progression of AD and developing relevant therapeutics is vast. Pathologically hallmarks of AD include the extra-neuronal clustering of Aβ plaques and the formation of intraneuronal neurofibrillary tangles (NFTs) which result in neuronal synaptic dysfunction [10, 11]. Aβ plaques formation is found in basal ganglia, amygdala, diencephalon, hippocampus, temporal and later it is found in the brain stem, cerebellar cortex and mesencephalon. The high levels of Aβ plaques are responsible for tau formation in the entorhinal, transentorhinal as well as locus coeruleus areas of the brain. It spreads to the hippocampus and neocortex in the critical stage [12].

Aβ plaque is formed from proteolysis of APP followed by two pathways (1) non-amyloidogenic pathway (physiological pathway), (2) amyloidogenic pathway (Figure 1). APP is a transmembrane glycoprotein whose a large portion toward the cytoplasm and a short portion inside the lumen. The non-amyloidogenic pathway prevents to the formation of toxic Aβ as APP is first cleaved by α-secretase and generates soluble fragments sAPPα and C83. These further cleaved by γ-secretase and produced non-toxic p3 and APP Intracellular Domain (AICD). On the other hand, the amyloidogenic pathway, neurotoxic Aβ formed through cleavage of APP by β-secretase (BACE1) followed by γ-secretase and formed sAPPβ, C99, Aβ, and AICD. These fragments are functionally active and influence or modulate signaling proteins [13]. Aβ oligomerization led to the formation of senile plaques and blockage the nerve transmission. There are mainly two types of Aβ isoforms soluble Aβ40 and insoluble Aβ42. The latter Aβ is more prone to aggregate and high concentration found in AD patients [14, 15]. The Aβ polymers aggregation results in blockage of ion channel, decreased energy metabolism, alteration in calcium homeostasis, diminish glucose regulation, and increases mitochondrial stress level, which further plays role in abnormality in neuronal health and causes neuronal death [12, 16]. Moreover, the AICD acts differently according to its generating pathways. The AICD from non-amyloidogenic pathways is degrading rapidly, but in the case of the amyloidogenic pathway, AICD behaves as a regulator for other genes [17].

Figure 1.

Amyloidogenic and non-amyloidogenic pathways. APP = amyloid precursor protein; ACID = APP intracellular domain; NFTs = neurofibrillary tangles.

Intra-neuronal deposition of NFTs are another pathophysiological hallmark of AD. NFTs were predominantly consisted of hyper-phosphorylated tau due to imbalance between phosphorylation and de-phosphorylation of tau [18]. Kinases are involved in the phosphorylation of tau protein, while phosphatases remove the phosphate residues. Tau proteins are microtubule-associated proteins that help vesicle transportation by stabilizing the microtubule. Microtubules are essential for axonal transport, neuronal structure, and neural plasticity [19]. Heavily phosphorylated tau may lose its capacity to stabilize itself and begin to self-form NFTs. Neurons cannot operate correctly without a full system of microtubules, and they eventually die. Tauopathies are considered to be an indicator of the severity of AD [20].

Figure 2.

Schematic diagram of miRNA synthesis; ago: argonaute protein; miRisc: RNA-induced silencing complex.


3. MicroRNA

MicroRNA (miRNA/miR) is a kind of non-coding RNA that has 22–23 nucleotides. They regulate gene expression by interacting with the 3′-untranslated region (3′UTR) of mRNA. Thus, miRNA inhibits translation or destroys the targeted mRNA as a result of this event [21, 22]. Biogenesis of miRNA occurs with both canonical pathways as well as non-canonical pathways. However, miRNAs are processed dominantly by the canonical biogenesis pathway [23]. The detailed process of miRNA biogenesis by canonical pathway is illustrated in Figure 2. RNA polymerase II in the nucleus transcribed miRNAs gene to primary miRNAs (pri-miRNAs). In collaboration with Pasha/DGCR8, the RNase III enzyme, Drosha converts these pri-miRNAs into precursor miRNAs (pre-miRNAs) and then these pre-miRNAs are transported to the cytoplasm by Exportin 5 [24, 25]. These pre-miRNAs are of approximately 70 nucleotides in a hairpin structure. Pre-miRNAs features a hairpin loop structure that is identified by dicer present in the cytoplasm for cleavage, resulting in the formation of mature miRNAs which is a double-stranded miRNA duplex [25]. The miRNA-induced silencing complex (miRISC) is formed when one of these strands of the mature duplex is loaded onto a member of the Argonaute (Ago) family of proteins, whereas the other strand of the mature duplex is normally destroyed. RISCs mediate gene silencing by recognizing the 3′ untranslated region (3′ UTR) of target mRNA [24, 25].

Figure 3.

A schematic diagram of the Aβ hypothesis in AD pathogenesis and involvement of miRNA in each stage. The amyloid beta is produced as a result of processing the APP (amyloid precursor protein) by a sequential enzyme digescted by BACE1 and γ-secretase generate imbalance between the clearance and production of Aβ which is the key factor of AD.


4. Association of microRNAs and Alzheimer’s disease

Pathologically, AD is generated by impaired metabolism of Aβ and the imbalance between the hyper-phosphorylated and de-phosphorylated forms of tau. Although these clinical-pathological features of AD are extensively established, therapies aiming at lowering synthesis or eliminating misfolded proteins are very limited [21]. Only four medicines, including three cholinesterase inhibitors (donepezil, rivastigmine, and galanthamine) and the glutamate regulator memantine, were licensed by the US Food and Drug Administration (FDA) for the treatment of cognitive impairment and dysfunction in symptomatic AD until June 2021. These symptomatic therapies can only delay rather than stop disease development [26, 27]. On June 7, 2021, Aducanumab, the first targeted Alzheimer’s therapy was approved by the FDA to treat patients with AD [27]. Thus, a different approach has centred on genetics, with several genes encoding proteins in central nervous system (CNS ) offered as candidates to explain AD etiology [21]. Earlier studies showed miRNA play role in the elaborating different types of pathogenic diseases including cardiovascular, cancer, and neurological disorders [28, 29]. Numbers of studies show the involvement of miRNAs in the pathogenesis and their therapeutic potential in various neurodegenerative diseases including AD, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Prion diseases [30, 31]. AD study indicates that miRNA may be helpful for the regulation of genes, expressions of proteins, and changes in phenotype in human diseases. Some research studies show the abnormal regulation of miRNA-dependent genes which are responsible for the formation and deposition of Aβ plaques as well as NFTs and consequently neuronal-degeneration [32, 33, 34, 35]. The focus of this review is the implication of the miRNAs in the two most well-recognized theories of AD pathogenesis: the Aβ hypothesis (Figure 3) and the tau hypothesis (Figure 4).

4.1 MicroRNAs involved in the regulation of APP expression

Although APP regulation is challenging, the research of regulatory processes indicate the prognosis of Alzheimer’s patients (Figure 3). Some scientific evidence shows that miR-106b regulates APP expression by binding on the 3′UTR region of APP [33]. The miR-101 [36], miR-16 [37], and miR-153 [38] are found APP negative regulators in in-vitro studies as well as in-vivo studies.

4.2 MicroRNAs involved in the regulation of BACE1 expression

It has been found that BACE-1 expression and activity are regulated by some miRNAs like the miR-29 family. BACE-1 expression level is increased with decreased expression of miR29a/b1 in sporadic AD brain. Moreover, it was also validated that low-level expression of miR29a/b1 is responsible for the pathogenesis of AD by promoting the production of Aβ plaques [39]. Another study found that downregulation of BACE1 is found in a cell line (SH-SY5Y) with overexpression of miR-29c via binding of BACE-13′ UTR [40]. Another study revealed that miR-107 regulates the expression of BACE1 in cell culture by binding the 3′UTR of BACE1 [41]. It was demonstrated that the BACE1 mRNA level was negatively affected by miR-107. Therefore, miR-107 could be a potential drug target [42] as it prevents the Aβ induced neurotoxicity and blood barrier dysfunction [43]. Certain miRNAs which are negative regulators of BACE1 expression by binding with 3′ UTR of BACE1 include miR-298/328 [44], miR-135a [45], miR135b [46], miR-186 [47], miR-195 [48], miR-200b [45], and miR-339-5P (Figure 3) [49].

Figure 4.

The imbalance between the hyper-phosphorylated and de-phosphorylated processes of Tau could lead to the formation of NFTs. The miRNAs involved in the phosphorylated and de-phosphorylated processes play a role in AD pathogenesis.

4.3 Role of MicroRNAs in Aβ clearance

The deposition of Aβ occurred due to an imbalance between production and clearance of Aβ. Several studies show that certain microRNAs are involved in the clearance of Aβ. The upregulation of miR-128 can alter the Aβ clearance by targeting the lysosomal enzyme system in monocytes of AD sporadic patients. The breakdown of Aβ plaque in Alzheimer’s patients improves when miR-128 is blocked in monocytes [50]. In addition, miR-34a was also involved in digesting the Aβ, thus improving the clearance of overexpressed Aβ [51]. miR-155, 154, 200b, 27b, 128 immune-related microRNA allegedly contribute to the process of Aβ clearance mediated by blood-derived monocytes (BDMs) when expressed variably in the CCL2/CCR2 (chemokine/chemokine receptor) axis [52]. miR-302 may attenuate Aβ induced neuronal toxicity in the brain of Alzheimer’s patients via PTEN/ AKT/Nrf2/Ho-1 pathway. miR-137 may reduced Aβ induced toxicity of neurons with the help of NF-kβ by TNFAIP1 expression repressing in N2a cells [53].

4.4 MicroRNAs targeting neurofibrillary tangles

The expression levels of miR 26b [54], miR-125b [55, 56], miR-138 [57], and miR-146a [58] have been shown to be considerably up-regulated while miR-132/212 down-regulated [59] in Alzheimer’s patients. Overexpression of miR-125b inhibited the two phosphatases i.e., PPP1CA and DUSP6 which further causes tau hyperphosphorylation while kinase expression/activity and tau phosphorylation were reduced when miR-125b was inhibited [55]. miR-146a was discovered to specifically target the coiled-coil containing protein kinase1 (ROCK1) in brain cells, and inhibiting ROCK1 might cause aberrant tau phosphorylation [58]. Reports showed that miR-138 was found to promote tau phosphorylation via directly targeting the retinoic acid receptor alpha (RARA)/glycogen synthase kinase-3b (GSK-3b) pathway in HEK293/tau and N2a/APP cells [57]. The increased levels of miR-26b in post-mitotic neurons led to the pathophysiology of AD via cell cycle entrance, tau hyper-phosphorylation, and death [54] (Figure 4).


5. MicroRNAs as possible treatment tools in Alzheimer’s disease

The usage of miRNA in the treatment of the disorder is developing fast. In 2018, the FDA accepted the primary miRNA-founded therapy for the cure of the infrequent progressive polyneuropathy produced by hereditary transthyretin-mediated amyloidosis (hATTR) known as amyloid polyneuropathy [60]. The fact that miRNAs alter (or control) the expression of potential genes in AD has prompted researchers to pursue miRNA-based therapeutic options. The treatment modifications of miRNA are carried out in two different ways: first, the functioning of miRNAs is suppressed by oligonucleotides that target miRNAs are known as antagomirs while in a second way, synthetic oligonucleotides are used which plays the same role as endogenous miRNA (act as miRNA mimics) [61, 62]. Thus, a miRNA mimetic or antagonist could be evaluated as a treatment tool. It was also observed that increased miRNA expression can counter the accumulation of Aβ and tau in cell and animal models of AD. In transgenic mice model, the family of miR-200 (miR-200b and miR-200c) were recognized as Aβ secretion regulators by modulating mTOR in primary type of neurons [63, 64, 65]. The same effect of downregulation in Aβ production was seen after miR-330 upregulation in mice model of AD by activating the MAPK pathway [66]. In in-vitro AD model, inhibition of Aβ accumulation was observed by miR-15b by targeting enzyme BACE1 and NF-κB signaling [67]. Similarly, in-vitro studies suggested that miR-124 works as a basic regulating factor in process of AD by targeting BACE1 and controlling BACE1 gene expression [68]. To understand the contribution of miR-124 in the pathogenesis of AD, the brain tissues of 35 cases of sporadic AD and control subjects were analyzed for miR-124 expression by the qRT-PCR technique. The reduction in the level of miR-124 expression was seen in AD brain tissues with comparison to the control group. In addition, inhibition of miR-124 significantly increased BACE1 levels in human neuroblastoma cells (SH-SY5Y), while miR-124 overexpression significantly suppressed BACE1 [69]. MiR-219 was shown to be downregulated in severe primary age-related tau pathology as evaluated by the RT-qPCR study. In addition, it was shown in the Drosophila model (which produces human tau) that the reduction of miR-219 increases tau toxicity, while the overexpression of miR-219 partially reverses this effect [70]. In in-vivo studies for cognitive capacity in SAMP8 mice, it was found that the miR-214-3p suppresses the autophagy and apoptosis of hippocampus neurons in sporadic Alzheimer’s disease (SAD) [71]. It was also found that miR-let-7f-5p had anti-apoptotic and protective effect in Aβ induced neurotoxicity on grafted mesenchymal stem cells by targeting caspase-3 in AD model [72]. These findings suggested that miR-214-3p and let-7f-5p are having anti-apoptotic activity and increase the cell viability of neurons, therefore, it can be therapeutically important [71, 72]. One literature reported that NF-kB was inactivated by upregulation of PPAR-γ in mouse cortical neurons and Neuro2a cells. MiR-128 targeted the PPAR-γ and by targeting PPAR-gamma reduced the Aβ mediated cytotoxicity in the studies [73]. It was observed that overexpression of both miR-125b [55] and miR-146a [58] stimulates the apoptosis of neuron and tau phosphorylation in cellular and molecular AD models. In recent years many chemicals are studied that can affect miRNAs pharmacologically. Anti-inflammatory medications may be effective in preventing the course of AD through modulating miRNAs. Additionally, naturally obtained compounds are recognized for their possible effect as neuroprotective agents in AD, like resveratrol [74] and osthole [75], which appear to be effective by modulating a specific type of miRNA and activate processes like autophagy and neuronal regeneration. Exosomes, tiny vesicles generated by neurons and glial cells, may also be used as therapies to give miRNAs and/or short interfering RNA (siRNA) to patients, according to new research. Multitargeted treatment methods, such as the use of acetylcholinesterase (AChE) inhibitors in conjunction with the manipulation of certain miRNAs, are also being investigated. Approaching miRNAs as therapeutic targets has two major drawbacks: (1) their ability to control several transcripts (up to hundreds) at once, and (2) the difficulty of achieving effective miRNA delivery.


6. MicroRNAs as possible diagnostic biomarkers in Alzheimer’s disease

AD is categorized, according to biochemical and clinical changes, into three different stages: pre-clinical i.e., early asymptomatic, mild cognitive impairment (MCI), and eventual dementia [76]. The majority of currently known biomarkers and approaches are focused on the late stages of the illness and may be categorized as follows: (1) neuropsychological tests, (2) neuroimaging techniques, and (3) protein biomarkers in the cerebrospinal fluid (CSF) [25]. Neuropsychological tests include cognitive assessments such as the Mini-Mental State Examination (MMSE) for early diagnosis to track cognitive changes over time and quantify the severity of cognitive impairment; however, this method is limited by factors such as the patient’s familiarity with the test and their educational attainment, which limits its sensitivity and specificity [77]. Neuroimaging examinations include fluorodeoxyglucose (FDG)-positron emission tomography (PET) and magnetic resonance imaging (MRI) for monitoring functional abnormalities as well as pathophysiological alterations such as medial temporal lobe atrophy and metabolic problems that can develop without evident cognitive impairment. Though this approach is viable, it has significant time and expense constraints. There are just a few laboratories that provide neuroimaging examinations. As a result, only a limited proportion of patients have access to neuroimaging [78]. Currently, protein biomarkers are the best biomarkers for monitoring AD and clinical research. They include Aβ1–40, Aβ1–4, phosphorylated tau (ptau), and total tau (t-tau) proteins in the CSF. However, a lumbar puncture is required to get CSF, which is invasive and not well tolerated by patients [78]. The identification of disease-causing genes is also a viable option. Simple, efficient, and inexpensive biomarkers for AD diagnosis are still lacking, especially in the early stages of the illness [25]. Several pieces of literature have found that particular miRNA species found in the biofluid of Alzheimer’s patients correlate with clinical alterations [22, 79, 80, 81]. Thus, miRNA emerges as a potential biomarker for initial diagnosis of AD as they are present in circulatory fluids which include CSF, seminal fluid, peritoneal fluid, amniotic fluid, pleural fluid, bronchial secretions seminal fluid, serum, plasma, and various other biological fluids [82, 83]. Circulatory miRNAs are a possible diagnostic biomarker for the illness because of their consistency and large quantity. miRNAs are when enwrapped in liposomes or attached to lipoproteins in the CSF, serum, or plasma, they are more stable and may endure harsh environmental conditions [84]. Furthermore, miRNAs may be acquired and measured with ease utilizing real-time PCR, next-generation sequencing (NGS), or microarray. Bio-molecules found in biological fluids such as CSF, tear, urine, and blood are being studied for their possible role in detecting disease progression in Alzheimer’s patients. According to previous research, miRNA is a modulator of the pathogenic state exhibited in AD [85]. Several miRNAs like miR-26b [54], miR-34a/c, miR125b, miR-210, and miR-146b are shown to change in blood and brain in Alzheimer’s patients, although the direction of changes is not always consistent between both miRNA sources [22, 86]. Furthermore, miRNA isolated from Alzheimer’s patients’ blood plasma and serum including miR-545-3p, miR-107, miR-15b-5p, miR-191-5p has been expected as potential AD biomarkers [22]. MiR-455-3p has emerged as a possible AD biomarker since growing levels in serum are commensurate with levels in AD brains, fibroblasts, lymphocytes, and even AD transgenic models [87]. This emerges the need to further explore the potential of a single miRNA to identify prodromal AD. A panel of miRNAs implicated in pathological processes underlying AD, such as neuroinflammation, has emerged as a diagnostic tool for AD prediction. While much work is being done on miRNA-based biomarkers for AD, few studies in the area have looked at the link between AD biomarkers and synaptic function modulation. Table 1 summarizes the most important findings in synaptic-related miRNAs obtained from circulating biofluids of AD patients and their potential value as biomarkers. The majority of studies have been done in blood samples, including serum and plasma, indicating a desire to investigate less invasive biomarkers. Certain studies reported earlier demonstrated that reproducibility between studies might be challenging even when miRNAs are obtained from the same sample source. As an example, the drop in miR-132 in serum from mild cognitive impairment (MCI) and AD patients [102, 107], has been replicated in plasma sample [131], although Sheinerman and team found an increase in MCI individuals [105], MiR-132, along with miR-206, which is similarly downregulated in MCI serum, has been proposed as part of a serum-based signature for MCI identification [102]. The adoption of miRNA-based signatures, which take into account the simultaneous modification of many miRNAs, can result in greater accuracy, sensitivity, and specificity values, which could be beneficial for future diagnostic tools. Another signature based on serum-miRNA levels, including synaptic-related miR-23a, miR-29a, and miR-125b has shown promising results in distinguishing Alzheimer’s patients from healthy cognitive controls (HCC) [92]. Although results are inconsistent between researches, the diagnostic usefulness of the miR-29a/b family has been examined in serum and CSF [39, 92, 96, 100, 132]. The modification of these miRNAs in biological fluids during AD pathology appears to be obvious. MiR-125b and miR-23a, on the other hand, have continuously increased in serum, demonstrating a strong ability to differentiate between AD and control participants [92, 115]. MiR-125b’s potential has also been investigated in CSF, where it has subsequently been offered as a specialized tool [116]. As previously reported, an increase in associated miR-125a levels has been seen in CSF from AD patients, suggesting that it might be used as a biomarker [100, 107]. Limited literature has looked at miRNA levels over time to see whether they might predict the development of MCI into AD. Beneficial diagnostic tool for classify MCI from AD include miR-206 [103], miR-146a, and miR-181a [113], miR-181c [88, 92], miR-181a and miR-181c [105], miR-92a-3p, and miR-210-3p [86], miR-107 [133].

TargetmiRNAFunctionBio-fluidsUpregulation (Up) or Downregulation (Down)References
APPmiR-106bRegulate APP expressionSerumUp[33, 88, 89]
miR-101Negative regulator of APP expressionSerumUp[36, 89, 90]
miR-16Decreased expression of miR-16 lead to accumulation of APP protein in ADBloodUp[37, 91]
ADAM10miR-23aNon-amyloidogenic APP processingSerumUp[92, 93]
miR-107PlasmaDown[41, 94]
miR-451Plasma-derived extracellular vesiclesDown[93, 95]
BACE1miR-9TNF-α,ephrin-A2 and APP cleavageCSF exosomesUp[96, 97, 98, 99]
miR-107PlasmaDown[41, 94]
miR-29aSerumUp[39, 96, 100]
miR-29bSerumUp[39, 96, 101]
BDNFmiR-206Growth factor involved in synapse maturationSerum and plasmaUp[102, 103, 104]
CREB1miR-134Transcription factor involved in synaptic plasticityPlasmaUp[105, 106]
DLG4miR-125aScaffold protein (PSD-95)CSF and SerumUp[107, 108]
DPYSL2miR-181cAxon guidance (CRMP-2)PlasmaUp[86, 98, 109]
EFNA3miR-210(Ephrin-A3) Axon guidancePlasmaUp[86, 110]
GRIA1miR-137Synaptic transmissionSerumDown[96, 111]
miR-501SerumDown[78, 112]
GRIA2miR-181aNeurotransmitter releaseBloodUp[113, 114]
GRIN2AmiR-125bSynaptic transmissionCSF and SerumDown[115, 116, 117]
GRIN2BmiR-34aSynaptic transmissionPlasmaUp[101, 118, 119]
IGF1miR-26bGrowth factor involved in synapse maturationSerumUp[116, 120, 121]
MME (NEP)miR-26bNeurite outgrowthSerumUp[116, 121, 122]
SYNmiR-106bInhibit tau phosphorylationSerumUp[88, 89, 123]
STIM2miR-128NMDA-evoked intracellular Ca2+PlasmaUp[105, 124, 125]
SIRT1miR-132Acetylation of substrates related to learning and memorySerumDow[93, 102]
SYT1miR-146aTrafficking/neurotransmitter releaseBloodUp[21, 113, 126]
CSF and plasmaDown[101]
TMOD2miR-191Actin filament organizationPlasmaDown[127, 128]
VAMP2miR-34cNeurotransmitter release VesiclePlasmaUp[129, 130]

Table 1.

Changes in the level of MiRNAs in the blood, plasma/serum and cerebral-spinal fluid (CSF) of AD patients with their targets and functions.

The potential utility and benefits of miRNAs as early biomarkers for AD underscore the urgent need for protocol standardization as a critical tool for accelerating development in generating more accurate findings and bringing breakthroughs to the clinics. Molecular diagnostics companies like DiamiR are already developing and commercializing miRNA-based technologies, demonstrating the progress made in the field and the real possibilities of using miRNAs as biomarkers for AD not only in screening and diagnosis but also as a useful tool for bettering the condition of clinical trial participants.


7. Conclusion

MiRNAs play an important role in the progression of AD. Alzheimer’s investigation indicates that miRNA may assist to gene regulation, protein-protein expressions, and phenotypic changes in diseases condition and some indication shows that aberrant regulation of miRNA-dependent genes are related to some cellular and molecular events which are liable for Aβ production, neurodegeneration, and NFTs formation. This review highlights the involvement of miRNAs in the regulation of APP expression, BACE1 expression and Aβ clearance. Thus, miRNA is possibly used as a treatment tool for AD. In addition to the therapeutic tool, microRNAs are also emerging as diagnostic tools because of their high sensitivity, efficiency, and specificity. It is found in biological fluids like CSF, extracellular fluid, pleural fluid, seminal fluid, bronchial secretions, breastmilk, serum, blood, plasma, etc. Thus, given the intricacy of AD development, illness history, and diagnosis, future treatment methods such as miRNA and anti-miRNA (antimiR, antagomir) techniques are needed:

  1. It will be coupled with improvements in the development of sensitive and precise neuroimaging and biofluid-based diagnostic tools for miRNA and other AD-relevant biomarkers,

  2. It will need to be simultaneous and multimodal, addressing numerous disease pathways, and neurological symptoms to block basic illness progression while minimizing ancillary off-target consequences,

  3. It will be used for screening in conjunction with basic medical care and as a second level diagnostic work-up for expert diagnosis and clinical treatment,

  4. It may entail correct medication therapy and distinct therapeutic development within the neurophysiological perspectives and the systems biology.


Conflict of interest

The authors declare no conflict of interest.



3’UTR3′-untranslated region
ACIDAPP intracellular domain
ADAlzheimer’s disease
ADAM10a disintegrin and metalloproteinase 10
Agoargonaute protein
AKTprotein kinase B
APPamyloid precursor protein
amyloid beta
BACE1β-site amyloid precursor protein cleaving enzyme 1
BDMsblood-derived monocytes
C83proteolytic products of APP
CCL2/CCR2chemokine (c-c motif) ligand 2/chemokine (c-c) receptor type 2
CREB1CAMP responsive element binding protein 1
CSFcerebrospinal fluid
DGCR8DiGeorge syndrome critical region 8
DLG4discs large homolog 4
DPYSL2dihydropyrimidinase-related protein 2
Drosharibonuclease III enzyme
DUSP6dual specificity phosphatase 6
EFNA3ephrin A3
Evsextracellular vesicles
FTDfrontotemporal disorder
GRIA1glutamate receptor 1
GRIN2Bglutamate receptor ionotropic, NMDA 2B
GSK-3bglycogen synthase kinase-3β
hATTRhereditary transthyretin-mediated amyloidosis
HCChealthy cognitive controls
HEK293human embryonic kidney cell-line
Ho-1heme oxygenase 1
IGF1insulin-like growth factor 1
MAPKmitogen-activated protein kinases
MCImild cognition impairment
MEF2Dmyocyte-specific enhancer factor 2D
MME (NEP)membrane metalloendopeptidase (neutral endopeptidase)
MMSEmini-mental state examination
MRImagnetic resonance imaging
mTORmammalian target of rapamycin
N2aneuro-2-a cell
NF-kβnuclear factor kappa beta
NFTsneurofibrillary tangles
NGSnext-generation sequencing
Nrf2nuclear factor erythroid 2-related factor 2
PETpositron emission tomography
PPARperoxisome proliferator- activated receptor gamma
PPP1CAPP1-alpha catalytic subunit gene
pri-miRNAsprimary miRNAs
PTENphosphatase and tensin homolog
RARAretinoic acid receptor alpha
RISCRNA-induced silencing complex
ROCK1Rho-associated, coiled-coil-containing protein kinase 1
SADsporadic Alzheimer’s disease
SAMP8senescence-accelerated mouse prone
sAPPsoluble amyloid precursor protein
SH-SY5Yhuman derived neuroblastoma cell line
siRNAsmall interfering RNAs
SIRT1silent mating type information regulation 2 homolog
STIM2stromal interaction molecule 2
SYN2synapsin II
TMOD2tropomodulin 2
TNFAIP1TNF alpha induce protein 1
VAMP2vesicle-associated membrane protein 2


  1. 1.Bekris LM, Yu CE, Bird TD, Tsuang DW. Genetics of Alzheimer disease. Journal of Geriatric Psychiatry and Neurology. 2010;23(4):213-227. DOI: 10.1177/0891988710383571
  2. 2.Goedert M, Spillantini MG. Tau mutations in frontotemporal dementia FTDP-17 and their relevance for Alzheimer’s disease. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2000;1502(1):110-121
  3. 3.Dermaut B, Kumar-Singh S, Rademakers R, Theuns J, Cruts M, Van Broeckhoven C. Tau is central in the genetic Alzheimer–frontotemporal dementia spectrum. Trends in Genetics. 2005;21(12):664-672
  4. 4.Chavali VD, Agarwal M, Vyas VK, Saxena B. Neuroprotective effects of ethyl Pyruvate against aluminum chloride-induced Alzheimer’s disease in rats via inhibiting toll-like receptor 4. Journal of Molecular Neuroscience. 2020;70(6):836-850
  5. 5.Tarawneh R, Holtzman DM. The clinical problem of symptomatic Alzheimer disease and mild cognitive impairment. Cold Spring Harbor Perspectives in Medicine. 2012;2(5):a006148. DOI: 10.1101/cshperspect.a006148
  6. 6.Sosa-Ortiz AL, Acosta-Castillo I, Prince MJ. Epidemiology of dementias and Alzheimer’s disease. Archives of Medical Research. 2012;43(8):600-608
  7. 7.Robinson M, Lee BY, Hane FT. Recent progress in Alzheimer’s disease research, part 2: Genetics and epidemiology. Journal of Alzheimer’s Disease. 2017;57(2):317-330. DOI: 10.3233/JAD-161149
  8. 8.Wong W. Economic burden of Alzheimer disease and managed care considerations. The American Journal of Managed Care. 2020;26(Suppl. 8):S177-S183
  9. 9.Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer’s disease. Alzheimer’s & Dementia. 2007;3(3):186-191
  10. 10.Rajmohan R, Reddy PH. Amyloid-beta and phosphorylated tau accumulations cause abnormalities at synapses of Alzheimer’s disease neurons. Journal of Alzheimer’s Disease. 2017;57(4):975-999. DOI: 10.3233/JAD-160612
  11. 11.Saxena B, Chavali VD. The role of toll like receptor 4 in pathogenesis of Alzheimer’s disease induced by aluminum chloride. International Journal of Emerging Technologies and Innovative Research. 2019;6(4):96-99
  12. 12.Tiwari S, Atluri V, Kaushik A, Yndart A, Nair M. Alzheimer’s disease: Pathogenesis, diagnostics, and therapeutics. International Journal of Nanomedicine. 2019;14:5541
  13. 13.Nhan HS, Chiang K, Koo EH. The multifaceted nature of amyloid precursor protein and its proteolytic fragments: Friends and foes. Acta Neuropathologica. 2015;129(1):1-19
  14. 14.Coronel R, Palmer C, Bernabeu-Zornoza A, Monteagudo M, Rosca A, Zambrano A, et al. Physiological effects of amyloid precursor protein and its derivatives on neural stem cell biology and signaling pathways involved. Neural Regeneration Research. 2019;14(10):1661
  15. 15.Kim J, Onstead L, Randle S, Price R, Smithson L, Zwizinski C, et al. Aβ40 inhibits amyloid deposition in vivo. Journal of Neuroscience. 2007;27(3):627-633
  16. 16.Sun X, Chen W-D, Wang Y-D. β-Amyloid: The key peptide in the pathogenesis of Alzheimer’s disease. Frontiers in Pharmacology. 2015;6:221
  17. 17.Zhang C, Khandelwal PJ, Chakraborty R, Cuellar TL, Sarangi S, Patel SA, et al. An AICD-based functional screen to identify APP metabolism regulators. Molecular Neurodegeneration. 2007;2(1):1-19
  18. 18.Ballatore C, Lee VM-Y, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nature Reviews Neuroscience. 2007;8(9):663-672
  19. 19.Lindwall G, Cole RD. Phosphorylation affects the ability of tau protein to promote microtubule assembly. Journal of Biological Chemistry. 1984;259(8):5301-5305
  20. 20.Iqbal K, Alonso AC, Chen S, Chohan MO, El-Akkad E, Gong C-X, et al. Tau pathology in Alzheimer disease and other tauopathies. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2005;1739(2-3):198-210
  21. 21.Angelucci F, Cechova K, Valis M, Kuca K, Zhang B, Hort J. MicroRNAs in Alzheimer’s disease: Diagnostic markers or therapeutic agents? Frontiers in Pharmacology. 2019;10:665
  22. 22.Swarbrick S, Wragg N, Ghosh S, Stolzing A. Systematic review of miRNA as biomarkers in Alzheimer’s disease. Molecular Neurobiology. 2019;56(9):6156-6167
  23. 23.O’Brien J, Hayder H, Zayed Y, Peng C. Overview of microRNA biogenesis, mechanisms of actions, and circulation. Frontiers in Endocrinology. 2018;9:402
  24. 24.Abe M, Bonini NM. MicroRNAs and neurodegeneration: Role and impact. Trends in Cell Biology. 2013;23(1):30-36
  25. 25.Wei W, Wang Z-Y, Ma L-N, Zhang T-T, Cao Y, Li H. MicroRNAs in Alzheimer’s disease: Function and potential applications as diagnostic biomarkers. Frontiers in Molecular Neuroscience. 2020;13:160
  26. 26.Long JM, Holtzman DM. Alzheimer disease: An update on pathobiology and treatment strategies. Cell. 2019;179(2):312-339
  27. 27.Yang P, Sun F. Aducanumab: The first targeted Alzheimer's therapy. Drug Discoveries & Therapeutics. 2021;15(3):166-168
  28. 28.Ha T-Y. MicroRNAs in human diseases: From cancer to cardiovascular disease. Immune Network. 2011;11(3):135-154
  29. 29.Lekka E, Hall J. Noncoding RNAs in disease. FEBS Letters. 2018;592(17):2884-2900
  30. 30.Junn E, Mouradian MM. MicroRNAs in neurodegenerative diseases and their therapeutic potential. Pharmacology & Therapeutics. 2012;133(2):142-150
  31. 31.Lau P, De Strooper B. Dysregulated microRNAs in neurodegenerative disorders. Seminars in Cell & Developmental Biology. 2010;21(7):768-773
  32. 32.Bazrgar M, Khodabakhsh P, Mohagheghi F, Prudencio M, Ahmadiani A. Brain microRNAs dysregulation: Implication for missplicing and abnormal post-translational modifications of tau protein in Alzheimer’s disease and related tauopathies. Pharmacological Research. 2020;155:104729
  33. 33.Hébert SS, Horré K, Nicolaï L, Bergmans B, Papadopoulou AS, Delacourte A, et al. MicroRNA regulation of Alzheimer’s amyloid precursor protein expression. Neurobiology of Disease. 2009;33(3):422-428
  34. 34.Kou X, Chen D, Chen N. The regulation of microRNAs in Alzheimer’s disease. Frontiers in Neurology. 2020;11:288
  35. 35.Thomas L, Florio T, Perez-Castro C. Extracellular vesicles loaded miRNAs as potential modulators shared between glioblastoma, and Parkinson’s and Alzheimer’s diseases. Frontiers in Cellular Neuroscience. 2020;14:360
  36. 36.Vilardo E, Barbato C, Ciotti M, Cogoni C, Ruberti F. MicroRNA-101 regulates amyloid precursor protein expression in hippocampal neurons. Journal of Biological Chemistry. 2010;285(24):18344-18351
  37. 37.Liu W, Liu C, Zhu J, Shu P, Yin B, Gong Y, et al. MicroRNA-16 targets amyloid precursor protein to potentially modulate Alzheimer's-associated pathogenesis in SAMP8 mice. Neurobiology of Aging. 2012;33(3):522-534
  38. 38.Long JM, Ray B, Lahiri DK. MicroRNA-153 physiologically inhibits expression of amyloid-β precursor protein in cultured human fetal brain cells and is dysregulated in a subset of Alzheimer disease patients. Journal of Biological Chemistry. 2012;287(37):31298-31310
  39. 39.Hébert SS, Horré K, Nicolaï L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, et al. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/β-secretase expression. Proceedings of the National Academy of Sciences. 2008;105(17):6415-6420
  40. 40.Lei X, Lei L, Zhang Z, Zhang Z, Cheng Y. Downregulated miR-29c correlates with increased BACE1 expression in sporadic Alzheimer’s disease. International Journal of Clinical and Experimental Pathology. 2015;8(2):1565
  41. 41.Wang W-X, Rajeev BW, Stromberg AJ, Ren N, Tang G, Huang Q , et al. The expression of microRNA miR-107 decreases early in Alzheimer's disease and may accelerate disease progression through regulation of β-site amyloid precursor protein-cleaving enzyme 1. Journal of Neuroscience. 2008;28(5):1213-1223
  42. 42.Parsi S, Smith PY, Goupil C, Dorval V, Hébert SS. Preclinical evaluation of miR-15/107 family members as multifactorial drug targets for Alzheimer's disease. Molecular Therapy-Nucleic Acids. 2015;4:e256
  43. 43.Shu B, Zhang X, Du G, Fu Q , Huang L. MicroRNA-107 prevents amyloid-β-induced neurotoxicity and memory impairment in mice. International Journal of Molecular Medicine. 2018;41(3):1665-1672
  44. 44.Boissonneault V, Plante I, Rivest S, Provost P. MicroRNA-298 and microRNA-328 regulate expression of mouse β-amyloid precursor protein-converting enzyme 1. Journal of Biological Chemistry. 2009;284(4):1971-1981
  45. 45.Liu C-G, Wang J-l, Li L, Xue L-X, Zhang Y-Q , Wang P-C. MicroRNA-135a and-200b, potential biomarkers for Alzheimer′ s disease, regulate β secretase and amyloid precursor protein. Brain Research. 2014;1583:55-64
  46. 46.Zhang Y, Xing H, Guo S, Zheng Z, Wang H, Xu D. MicroRNA-135b has a neuroprotective role via targeting of β-site APP-cleaving enzyme 1. Experimental and Therapeutic Medicine. 2016;12(2):809-814
  47. 47.Kim J, Yoon H, Chung D, Brown JL, Belmonte KC, Kim J. miR-186 is decreased in aged brain and suppresses BACE 1 expression. Journal of Neurochemistry. 2016;137(3):436-445
  48. 48.Zhu H-C, Wang L-M, Wang M, Song B, Tan S, Teng J-F, et al. MicroRNA-195 downregulates Alzheimer’s disease amyloid-β production by targeting BACE1. Brain Research Bulletin. 2012;88(6):596-601
  49. 49.Long JM, Ray B, Lahiri DK. MicroRNA-339-5p down-regulates protein expression of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer disease subjects. Journal of Biological Chemistry. 2014;289(8):5184-5198
  50. 50.Tiribuzi R, Crispoltoni L, Porcellati S, Di Lullo M, Florenzano F, Pirro M, et al. miR128 up-regulation correlates with impaired amyloid β (1-42) degradation in monocytes from patients with sporadic Alzheimer’s disease. Neurobiology of Aging. 2014;35(2):345-356
  51. 51.Zhao Y, Jaber V, Lukiw WJ. Over-expressed pathogenic miRNAs in Alzheimer’s disease (AD) and prion disease (PrD) drive deficits in TREM2-mediated Aβ42 peptide clearance. Frontiers in Aging Neuroscience. 2016;8:140
  52. 52.Guedes JR, Santana I, Cunha C, Duro D, Almeida MR, Cardoso AM, et al. MicroRNA deregulation and chemotaxis and phagocytosis impairment in Alzheimer's disease. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. 2016;3:7-17
  53. 53.He D, Tan JZ, J. miR-137 attenuates Aβ-induced neurotoxicity through inactivation of NF-κB pathway by targeting TNFAIP1 in Neuro2a cells. Biochemical and Biophysical Research Communications. 2017;490(3):941-947
  54. 54.Absalon S, Kochanek DM, Raghavan V, Krichevsky AM. MiR-26b, upregulated in Alzheimer’s disease, activates cell cycle entry, tau-phosphorylation, and apoptosis in postmitotic neurons. Journal of Neuroscience. 2013;33(37):14645-14659
  55. 55.Banzhaf-Strathmann J, Benito E, May S, Arzberger T, Tahirovic S, Kretzschmar H, et al. Micro RNA-125b induces tau hyperphosphorylation and cognitive deficits in Alzheimer's disease. The EMBO Journal. 2014;33(15):1667-1680
  56. 56.Ma X, Liu L, Meng J. MicroRNA-125b promotes neurons cell apoptosis and Tau phosphorylation in Alzheimer’s disease. Neuroscience Letters. 2017;661:57-62
  57. 57.Wang X, Tan L, Lu Y, Peng J, Zhu Y, Zhang Y, et al. MicroRNA-138 promotes tau phosphorylation by targeting retinoic acid receptor alpha. FEBS Letters. 2015;589(6):726-729
  58. 58.Wang G, Huang Y, Wang L-L, Zhang Y-F, Xu J, Zhou Y, et al. MicroRNA-146a suppresses ROCK1 allowing hyperphosphorylation of tau in Alzheimer’s disease. Scientific Reports. 2016;6(1):1-12
  59. 59.Wang Y, Veremeyko T, Wong AH-K, El Fatimy R, Wei Z, Cai W, et al. Downregulation of miR-132/212 impairs S-nitrosylation balance and induces tau phosphorylation in Alzheimer's disease. Neurobiology of Aging. 2017;51:156-166
  60. 60.Luigetti M, Romano A, Di Paolantonio A, Bisogni G, Sabatelli M. Diagnosis and treatment of hereditary transthyretin amyloidosis (hATTR) polyneuropathy: Current perspectives on improving patient care. Therapeutics and Clinical Risk Management. 2020;16:109
  61. 61.Laina A, Gatsiou A, Georgiopoulos G, Stamatelopoulos K, Stellos K. RNA therapeutics in cardiovascular precision medicine. Frontiers in Physiology. 2018;9:953
  62. 62.Li Z, Rana TM. Therapeutic targeting of microRNAs: Current status and future challenges. Nature Reviews Drug Discovery. 2014;13(8):622-638
  63. 63.Fu J, Peng L, Tao T, Chen Y, Li Z, Li J. Regulatory roles of the miR-200 family in neurodegenerative diseases. Biomedicine & Pharmacotherapy. 2019;119:109409
  64. 64.Higaki S, Muramatsu M, Matsuda A, Matsumoto K, Satoh J-i, Michikawa M, et al. Defensive effect of microRNA-200b/c against amyloid-beta peptide-induced toxicity in Alzheimer's disease models. PLoS One. 2018;13(5):e0196929
  65. 65.Tramutola A, Triplett JC, Di Domenico F, Niedowicz DM, Murphy MP, Coccia R, et al. Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): Analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and late-stage AD. Journal of Neurochemistry. 2015;133(5):739-749
  66. 66.Zhou Y, Wang ZF, Li W, Hong H, Chen J, Tian Y, et al. Protective effects of microRNA-330 on amyloid β-protein production, oxidative stress, and mitochondrial dysfunction in Alzheimer’s disease by targeting VAV1 via the MAPK signaling pathway. Journal of Cellular Biochemistry. 2018;119(7):5437-5448
  67. 67.Li J, Wang H. miR-15b reduces amyloid-β accumulation in SH-SY5Y cell line through targetting NF-κB signaling and BACE1. Bioscience Reports. 2018;38(6):BSR20180051
  68. 68.Fang M, Wang J, Zhang X, Geng Y, Hu Z, Rudd JA, et al. The miR-124 regulates the expression of BACE1/β-secretase correlated with cell death in Alzheimer's disease. Toxicology Letters. 2012;209(1):94-105
  69. 69.An F, Gong G, Wang Y, Bian M, Yu L, Wei C. MiR-124 acts as a target for Alzheimer’s disease by regulating BACE1. Oncotarget. 2017;8(69):114065
  70. 70.Santa-Maria I, Alaniz ME, Renwick N, Cela C, Fulga TA, Van Vactor D, et al. Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau. The Journal of Clinical Investigation. 2015;125(2):681-686
  71. 71.Zhang Y, Li Q , Liu C, Gao S, Ping H, Wang J, et al. MiR-214-3p attenuates cognition defects via the inhibition of autophagy in SAMP8 mouse model of sporadic Alzheimer's disease. Neurotoxicology. 2016;56:139-149
  72. 72.Han L, Zhou Y, Zhang R, Wu K, Lu Y, Li Y, et al. MicroRNA let-7f-5p promotes bone marrow mesenchymal stem cells survival by targeting caspase-3 in Alzheimer disease model. Frontiers in Neuroscience. 2018;12:333
  73. 73.Geng L, Zhang T, Liu W, Chen Y. Inhibition of miR-128 abates Aβ-mediated cytotoxicity by targeting PPAR-γ via NF-κB inactivation in primary mouse cortical neurons and Neuro2a cells. Yonsei Medical Journal. 2018;59(9):1096-1106
  74. 74.Kou X, Chen N. Resveratrol as a natural autophagy regulator for prevention and treatment of Alzheimer’s disease. Nutrients. 2017;9(9):927
  75. 75.Song Y, Wang X, Wang X, Wang J, Hao Q , Hao J, et al. Osthole-loaded nanoemulsion enhances brain target in the treatment of Alzheimer’s disease via intranasal administration. Oxidative Medicine and Cellular Longevity. 2021;2021:8844455
  76. 76.Croisile B, Auriacombe S, Etcharry-Bouyx F, Vercelletto M. Les nouvelles recommandations 2011 du National Institute on Aging et de l’Alzheimer’s Association sur le diagnostic de la maladie d’Alzheimer : Stades précliniques, mild cognitive impairment et démence. Revue Neurologique. 2012;168(6):471-482
  77. 77.Norris DR, Clark MS, Shipley S. The mental status examination. American Family Physician. 2016;94(8):635-641
  78. 78.Hara N, Kikuchi M, Miyashita A, Hatsuta H, Saito Y, Kasuga K, et al. Serum microRNA miR-501-3p as a potential biomarker related to the progression of Alzheimer’s disease. Acta Neuropathologica Communications. 2017;5(1):1-9
  79. 79.Keller A, Backes C, Haas J, Leidinger P, Maetzler W, Deuschle C, et al. Validating Alzheimer's disease micro RNAs using next-generation sequencing. Alzheimer's & Dementia. 2016;12(5):565-576
  80. 80.Takousis P, Sadlon A, Schulz J, Wohlers I, Dobricic V, Middleton L, et al. Differential expression of microRNAs in Alzheimer's disease brain, blood, and cerebrospinal fluid. Alzheimer’s & Dementia. 2019;15(11):1468-1477
  81. 81.Wiedrick JT, Phillips JI, Lusardi TA, McFarland TJ, Lind B, Sandau US, et al. Validation of MicroRNA biomarkers for Alzheimer’s disease in human cerebrospinal fluid. Journal of Alzheimer’s Disease. 2019;67(3):875-891
  82. 82.Kumar S, Reddy PH. Are circulating microRNAs peripheral biomarkers for Alzheimer's disease? Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2016;1862(9):1617-1627
  83. 83.Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH, Lee MJ, et al. The microRNA spectrum in 12 body fluids. Clinical Chemistry. 2010;56(11):1733-1741
  84. 84.Van den Berg M, Krauskopf J, Ramaekers J, Kleinjans J, Prickaerts J, Briedé J. Circulating microRNAs as potential biomarkers for psychiatric and neurodegenerative disorders. Progress in Neurobiology. 2020;185:101732
  85. 85.Ludwig N, Leidinger P, Becker K, Backes C, Fehlmann T, Pallasch C, et al. Distribution of miRNA expression across human tissues. Nucleic Acids Research. 2016;44(8):3865-3877
  86. 86.Siedlecki-Wullich D, Català-Solsona J, Fábregas C, Hernández I, Clarimon J, Lleó A, et al. Altered microRNAs related to synaptic function as potential plasma biomarkers for Alzheimer’s disease. Alzheimer’s Research & Therapy. 2019;11(1):1-11
  87. 87.Kumar S, Reddy AP, Yin X, Reddy PH. Novel MicroRNA-455-3p and its protective effects against abnormal APP processing and amyloid beta toxicity in Alzheimer's disease. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2019;1865(9):2428-2440
  88. 88.Guo R, Fan G, Zhang J, Wu C, Du Y, Ye H, et al. A 9-microRNA signature in serum serves as a noninvasive biomarker in early diagnosis of Alzheimer’s disease. Journal of Alzheimer’s Disease. 2017;60(4):1365-1377. DOI: 10.3233/JAD-170343
  89. 89.Cheng A, Doecke JD, Sharples R, Villemagne VL, Fowler CJ, Rembach A, et al. Prognostic serum miRNA biomarkers associated with Alzheimer’s disease shows concordance with neuropsychological and neuroimaging assessment. Molecular Psychiatry. 2015;20(10):1188-1196
  90. 90.Long JML, DK. MicroRNA-101 downregulates Alzheimer’s amyloid-β precursor protein levels in human cell cultures and is differentially expressed. Biochemical and Biophysical Research Communications. 2011;404(4):889-895
  91. 91.Wu HZY, Thalamuthu A, Cheng L, Fowler C, Masters CL, Sachdev P, et al. Differential blood miRNA expression in brain amyloid imaging-defined Alzheimer’s disease and controls. Alzheimer's Research & Therapy. 2020;12(59):1-11
  92. 92.Barbagallo C, Mostile G, Baglieri G, Giunta F, Luca A, Raciti L, et al. Specific signatures of serum miRNAs as potential biomarkers to discriminate clinically similar neurodegenerative and vascular-related diseases. Cellular and Molecular Neurobiology. 2020;40(4):531-546
  93. 93.Siedlecki-Wullich D, Miñano-Molina AJ, Rodríguez-Álvarez J. microRNAs as early biomarkers of Alzheimer’s disease: A synaptic perspective. Cells. 2021;10(1):113
  94. 94.Wang J, Chen C, Zhang Y. An investigation of microRNA-103 and microRNA-107 as potential blood-based biomarkers for disease risk and progression of Alzheimer's disease. Journal of Clinical Laboratory Analysis. 2020;34(1):e23006
  95. 95.Gámez-Valero A, Campdelacreu J, Vilas D, Ispierto L, Reñé R, Álvarez R, et al. Exploratory study on microRNA profiles from plasma-derived extracellular vesicles in Alzheimer’s disease and dementia with Lewy bodies. Translational Neurodegeneration. 2019;8(1):1-17
  96. 96.Geekiyanage H, Jicha GA, Nelson PT, Chan C. Blood serum miRNA: Non-invasive biomarkers for Alzheimer's disease. Experimental Neurology. 2012;235(2):491-496
  97. 97.Riancho J, Vázquez-Higuera JL, Pozueta A, Lage C, Kazimierczak M, Bravo M, et al. MicroRNA profile in patients with Alzheimer’s disease: Analysis of miR-9-5p and miR-598 in raw and exosome enriched cerebrospinal fluid samples. Journal of Alzheimer's Disease. 2017;57(2):483-491
  98. 98.Schonrock N, Humphreys DT, Preiss T, Götz J. Target gene repression mediated by miRNAs miR-181c and miR-9 both of which are down-regulated by amyloid-β. Journal of Molecular Neuroscience. 2012;46(2):324-335
  99. 99.Schonrock N, Ke YD, Humphreys D, Staufenbiel M, Ittner LM, Preiss T, et al. Neuronal microRNA deregulation in response to Alzheimer's disease amyloid-β. PloS One. 2010;5(6):e11070
  100. 100.Müller M, Jäkel L, Bruinsma IB, Claassen JA, Kuiperij HB, Verbeek MM. MicroRNA-29a is a candidate biomarker for Alzheimer’s disease in cell-free cerebrospinal fluid. Molecular Neurobiology. 2016;53(5):2894-2899
  101. 101.Kiko T, Nakagawa K, Tsuduki T, Furukawa K, Arai H, Miyazawa T. MicroRNAs in plasma and cerebrospinal fluid as potential markers for Alzheimer's disease. Journal of Alzheimer's Disease. 2014;39(2):253-259
  102. 102.Xie B, Zhou H, Zhang R, Song M, Yu L, Wang L, et al. Serum miR-206 and miR-132 as potential circulating biomarkers for mild cognitive impairment. Journal of Alzheimer's Disease. 2015;45(3):721-731
  103. 103.Kenny A, McArdle H, Calero M, Rabano A, Madden SF, Adamson K, et al. Elevated plasma microRNA-206 levels predict cognitive decline and progression to dementia from mild cognitive impairment. Biomolecules. 2019;9(11):734
  104. 104.Lee ST, Chu K, Jung KH, Kim JH, Huh JY, Yoon H, et al. miR-206 regulates brain-derived neurotrophic factor in Alzheimer disease model. Annals of Neurology. 2012;72(2):269-277
  105. 105.Sheinerman KS, Tsivinsky VG, Abdullah L, Crawford F, Umansky SR. Plasma microRNA biomarkers for detection of mild cognitive impairment: Biomarker validation study. Aging (Albany NY). 2013;5(12):925
  106. 106.Bicker S, Lackinger M, Weiß K, Schratt G. MicroRNA-132,-134, and-138: A microRNA troika rules in neuronal dendrites. Cellular and Molecular Life Sciences. 2014;71(20):3987-4005
  107. 107.Denk J, Oberhauser F, Kornhuber J, Wiltfang J, Fassbender K, Schroeter ML, et al. Specific serum and CSF microRNA profiles distinguish sporadic behavioural variant of frontotemporal dementia compared with Alzheimer patients and cognitively healthy controls. PloS One. 2018;13(5):e0197329
  108. 108.Muddashetty RS, Nalavadi VC, Gross C, Yao X, Xing L, Laur O, et al. Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling. Molecular Cell. 2011;42(5):673-688
  109. 109.Zhou H, Zhang R, Lu K, Yu W, Xie B, Cui D, et al. Deregulation of miRNA-181c potentially contributes to the pathogenesis of AD by targeting collapsin response mediator protein 2 in mice. Journal of the Neurological Sciences. 2016;367:3-10
  110. 110.Pulkkinen K, Malm T, Turunen M, Koistinaho J, Ylä-Herttuala S. Hypoxia induces microRNA miR-210 in vitro and in vivo: Ephrin-A3 and neuronal pentraxin 1 are potentially regulated by miR-210. FEBS Letters. 2008;582(16):2397-2401
  111. 111.Loohuis NFO, Ba W, Stoerchel PH, Kos A, Jager A, Schratt G, et al. MicroRNA-137 controls AMPA-receptor-mediated transmission and mGluR-dependent LTD. Cell Reports. 2015;11(12):1876-1884
  112. 112.Hu Z, Zhao J, Hu T, Luo Y, Zhu JL, Z. miR-501-3p mediates the activity-dependent regulation of the expression of AMPA receptor subunit GluA1. Journal of Cell Biology. 2015;208(7):949-959
  113. 113.Ansari A, Maffioletti E, Milanesi E, Marizzoni M, Frisoni GB, Blin O, et al. miR-146a and miR-181a are involved in the progression of mild cognitive impairment to Alzheimer's disease. Neurobiology of Aging. 2019;82:102-109
  114. 114.Rodriguez-Ortiz CJ, Prieto GA, Martini AC, Forner S, Trujillo-Estrada L, LaFerla FM, et al. miR-181a negatively modulates synaptic plasticity in hippocampal cultures and its inhibition rescues memory deficits in a mouse model of Alzheimer’s disease. Aging Cell. 2020;19(3):e13118
  115. 115.Tan L, Yu J-T, Liu Q-Y, Tan M-S, Zhang W, Hu N, et al. Circulating miR-125b as a biomarker of Alzheimer’s disease. Journal of the Neurological Sciences. 2014;336(1-2):52-56
  116. 116.Galimberti D, Villa C, Fenoglio C, Serpente M, Ghezzi L, Cioffi SM, et al. Circulating miRNAs as potential biomarkers in Alzheimer's disease. Journal of Alzheimer's Disease. 2014;42(4):1261-1267
  117. 117.Edbauer D, Neilson JR, Foster KA, Wang C-F, Seeburg DP, Batterton MN, et al. Regulation of synaptic structure and function by FMRP-associated MicroRNAs miR-125b and miR-132. Neuron. 2010;65(3):373-384
  118. 118.Sarkar S, Engler-Chiurazzi E, Cavendish J, Povroznik J, Russell A, Quintana D, et al. Over-expression of miR-34a induces rapid cognitive impairment and Alzheimer’s disease-like pathology. Brain Research. 2019;1721:146327
  119. 119.Xu Y, Chen P, Wang X, Yao J, Zhuang S. miR-34a deficiency in APP/PS1 mice promotes cognitive function by increasing synaptic plasticity via AMPA and NMDA receptors. Neuroscience Letters. 2018;670:94-104
  120. 120.Liu H, Chu W, Gong L, Gao X, Wang W. MicroRNA-26b is upregulated in a double transgenic mouse model of Alzheimer's disease and promotes the expression of amyloid-β by targeting insulin-like growth factor 1. Molecular Medicine Reports. 2016;13(3):2809-2814
  121. 121.Satoh J-i, Kino Y, Niida S. MicroRNA-Seq data analysis pipeline to identify blood biomarkers for Alzheimer’s disease from public data. Biomarker Insights. 2015;10:21-31
  122. 122.Chu T, Shu Y, Qu Y, Gao S, Zhang L. miR-26b inhibits total neurite outgrowth, promotes cells apoptosis and downregulates neprilysin in Alzheimer’s disease. International Journal of Clinical and Experimental Pathology. 2018;11(7):3383-3389
  123. 123.Liu W, Zhao J, Lu G. miR-106b inhibits tau phosphorylation at Tyr18 by targeting Fyn in a model of Alzheimer's disease. Biochemical and Biophysical Research Communications. 2016;478(2):852-857
  124. 124.Deng M, Zhang Q , Wu Z, Ma T, He A, Zhang T, et al. Mossy cell synaptic dysfunction causes memory imprecision via miR-128 inhibition of STIM2 in Alzheimer's disease mouse model. Aging Cell. 2020;19(5):e13144
  125. 125.Sheinerman KS, Tsivinsky VG, Crawford F, Mullan MJ, Abdullah L, Umansky SR. Plasma microRNA biomarkers for detection of mild cognitive impairment. Aging (Albany NY). 2012;4(9):590
  126. 126.Prada I, Gabrielli M, Turola E, Iorio A, D’Arrigo G, Parolisi R, et al. Glia-to-neuron transfer of miRNAs via extracellular vesicles: A new mechanism underlying inflammation-induced synaptic alterations. Acta neuropathologica. 2018;135(4):529-550
  127. 127.Hu Z, Yu D, Gu Q-h, Yang Y, Tu K, Zhu J, et al. miR-191 and miR-135 are required for long-lasting spine remodelling associated with synaptic long-term depression. Nature Communications. 2014;5(1):1-17
  128. 128.Kumar P, Dezso Z, MacKenzie C, Oestreicher J, Agoulnik S, Byrne M, et al. Circulating miRNA biomarkers for Alzheimer's disease. PloS One. 2013;8(7):e69807
  129. 129.Bhatnagar S, Chertkow H, Schipper HM, Shetty V, Yuan Z, Jones T, et al. Increased microRNA-34c abundance in Alzheimer's disease circulating blood plasma. Frontiers in Molecular Neuroscience. 2014;7:2
  130. 130.Hu S, Wang H, Chen K, Cheng P, Gao S, Liu J, et al. MicroRNA-34c downregulation ameliorates amyloid-β-induced synaptic failure and memory deficits by targeting VAMP2. Journal of Alzheimer’s Disease. 2015;48(3):673-686. DOI: 10.3233/JAD-150432
  131. 131.Cha DJ, Mengel D, Mustapic M, Liu W, Selkoe DJ, Kapogiannis D, et al. miR-212 and miR-132 are downregulated in neurally derived plasma exosomes of Alzheimer’s patients. Frontiers in Neuroscience. 2019;13:1208
  132. 132.Villa C, Ridolfi E, Fenoglio C, Ghezzi L, Vimercati R, Clerici F, et al. Expression of the transcription factor Sp1 and its regulatory hsa-miR-29b in peripheral blood mononuclear cells from patients with Alzheimer’s disease. Journal of Alzheimer’s Disease. 2013;35(3):487-494
  133. 133.Beccia M, Ceschin V, Bozzao A, Romano A, Biraschi F, Fantozzi L, et al. Headache and visual symptoms in two patients with MRI alterations in posterior cerebral artery territory. Clinical Therapeutics. 2009;160(2):125-127

Written By

Heena Chauhan, Pawan Gupta and Bhagawati Saxena

Submitted: December 7th, 2021Reviewed: February 10th, 2022Published: April 23rd, 2022