Dysregulation and Diagnostic Potential of microRNA in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases and is considered to be the main cause of cognitive impairment in elderly people. The major symptom of AD is progressive dementia that eventually results in dysfunction of daily life. Due to the fact that AD has a long period of incubation before clinical symptoms emerge, the available therapeutic treatments can only improve the symptoms but not delay the progression of AD. Therefore, there is an urgent need to explore effective diagnostic approaches to catch and better treat the disease before clinical symptoms appear. Recent research revealed that abnormal expression of certain miRNA could have a crucial role in the pathological process of neurodegenerative disease including AD. Furthermore, given that AD patients show increased level of miRNAs in the blood and cerebrospinal fluid, miRNAs are considered promising non-invasive candidates for AD diagnosis and prognosis. Here, we reviewed the current research related to implications of miRNAs during the development of AD, summarized of actively used approaches to identifying potential miRNA biomarkers in body fluids, and discussed the diagnostic potential of microRNAs as biomarkers for AD.

Keywords

Alzheimer’s disease biomarkers microRNAs

INTRODUCTION

Alzheimer’s disease (AD), one of the principal causes of dementia among the elderly (60% ) [1, 2], is expected to afflict 80 million people by 2050 [3]. Five million new AD patients, about one every seven seconds, are diagnosed each year [4]. Because of the extensive impact of AD on both patients and their families, a deeper understanding of the mechanisms of this disease and potential cures for it is of great importance. The pathological characteristics of the disease include cortex atrophy, ventricle enlargement, cerebral cortical nerve cell loss, extracellular amyloid-β (Aβ) deposition, and intraneuronal neurofibrillary tangles (NFTs) [5, 6]. The hippocampus, a region involved in learning and memory, is affected by these pathologies in the very early stage of disease progression. Initially, the hippocampus shrinks in size, neurons are lost, and associated cognitive defects result. The manifest of clinical symptoms in AD patients indicates irreversible dysfunction and that neuron damage has already occurred [7 –12]. Therefore, treatment before the irreversible damage has occurred could prove to be most effective at preventing the pathological development of the disease [13]. Unfortunately, no diagnostic method to detect early stage markers of AD is available to date. Thus, developing diagnostic methods with high specificity and sensitivity for early AD is very necessary and worthy endeavor.

MicroRNAs (miRNAs) are non-coding evolutionary conserved RNAs consisting of 18–25 nucleotides. It has been reported that these RNAs can regulate gene expression by binding to the complementary regions of mRNA, hence inhibiting translation or inducing degradation (Fig. 1) [14 –17]. Recent research has indicated that miRNAs take part in several biological pathways, including protein synthesis, by regulating hundreds of target genes. A single miRNA can have numerous target genes [18]. A group of miRNAs with the same complementary sequence and target genes is called a miRNA “family” [19].

Studies have found nearly 1,500 miRNA genes in humans and 750 miRNA genes in mice. Some of these genes are only present in specific organs, tissues, or cells [20 –22]. Fewer than 40 miRNAs have been found in human brains, while approximately 300 miRNAs are expressed in mice brains [23, 24]. Importantly, some of the miRNAs are enriched in particular regions, cell types, or particular subcellular structures of the brain, such as synapses, dendrites, and axons. Thus, these miRNAs could provide possible markers for disease diagnosis [25 –27].

Numerous studies relate miRNAs to the pathogenesis of neurodegenerative diseases, and many of these studies confirm that miRNAs function in some way in the disease progression (Table 1). For example, several studies have demonstrated a decrease in miR-133b in the midbrain of PD patients [28]. Others have shown that in neurodegenerative diseases induced by prion, 15 miRNAs are deregulated [29]. The contribution of miRNAs to AD progress has also been discussed. In this review, we will discuss the known knowledge of miRNAs in AD pathology and its potential in early AD diagnosis.

MicroRNAs IN AD-RELATED PATHOLOGY

In 2007, Lukiw was the first to show alterations in specific miRNAs, miR-9, miR-125b, and miR-128, induced by the production of reactive oxygen species, likely generating neurotoxic metal sulfates in the hippocampus of AD patients [30]. Subsequent investigations have found that miRNAs show significant variation or decreased expression throughout different areas of the brain in AD patients. For example, miR-106b, miR-29a/b/c, and miR-107 are decreased in the AD hippocampus, and miR-181c and miR-101 are deregulated in the AD cortex. Several miRNAs, such as miR-212, show low concentrations in the white matter of AD brains, while it has been reported that miR-15 and miR-107 are decreased in the gray matter. In contrast to these miRNAs, other miRNAs, such as miR-125b, miR-128, and miR-146a [24 , 31–34], show increased levels in the AD brain. Interestingly, the levels of miR-132 and miR-219 are maintained in AD brains [32]. In past and ongoing studies, we have focused more on the analysis of upregulated miRNAs as downregulation of miRNA abundance may be, in part, a consequence of their relatively short half-life, and uncontrolled and rapid degradation, especially in human postmortem tissues with difficult-to-control variability in agonal processes and related effects of dying human brain tissues on biomolecular integrity [4].

miRNAs related to amyloid protein

Extracellular amyloid protein deposition is one of the most important pathological hallmarks of AD. Amyloid-β (Aβ) is the product of large amyloid-β protein precursor (AβPP), which is cleaved by secretase [35]. With regard to AD, a major question is whether miRNAs are capable of altering Aβ levels. Actually, evidence has shown that miRNAs can affect Aβ levels in different ways.

Firstly, several in vitro studies have revealed some miRNAs that can directly regulate AβPP expression, including miR-20a, miR-106a, miR-106b, miR-17-5p, miR-16, miR-101, miR-147, miR-153, and miR-520c [33 , 37]. Among these miRNAs, miR-106b and miR-101 expression are decreased in AD brains [38], which subsequently result in increased AβPP expression and Aβ production. Further in vivo investigations are needed to determine whether these miRNAs actually contribute to regulating AβPP expression. More interestingly, AD-specific polymorphisms was reported to influence the AβPP-modulating activity of miR-147 and miR-20a [33, 39], thus it is intriguing to assume that that these polymorphisms could possibly influence the AD risk by affecting regulation of AβPP expression through modifying miRNA activity.

Secondly, miRNAs is associated with regulation of AβPP alternative splicing [40, 41]. There exist three major isoforms of AβPP (AβPP751, AβPP770, and AβPP695) generated by alternative splicing in humans. Changes in neuronal AβPP isoform expression are associated with Aβ production. Recent studies suggested the involvement of microRNAs n the fine-tuning of AβPP alternative splicing in neurons. In vivo experiments showed that reduced expression of miRNAs in post-mitotic neurons could be responsible for AβPP mRNA splicing. MiR-124 is downregulated in AD brain, and considering the key role of miR-124 plays in neuronal maintenance and splicing, it can be hypothesized that miR-124 is involved in splicing regulation of AβPP. Actually, gain-of-function experiments of MiR-124 have showed that miR-124 overexpression in cells causes a shift in neuronal gene expression patterns through interacting with its target gene— poly-pyrimidine tract binding protein 1 (PTBP1) [42, 43].

Moreover, miRNAs is associated with cleavage of AβPP. Three families of secretases contribute to AβPP cleavage. Cleavage of AβPP by α-secretase was in a non-amyloidogenic pathway, which precludes the formation of Aβ generates soluble AβPPα (sAβPPα) and a C-terminal fragment (c83) fragment. It has been suggested that disinterring and metalloproteinase domain-containing protein (ADAM) serves as an α-secretase. ADAM10 is a member of ADAM family, and proteolytic processing of the AβPP by ADAM10 protects the brain from the production of the Aβ. Studies showed that MiR-144 level is increased in AD patients and miR-144 acts as a negative regulator of ADAM10, suggesting that upregulation of miR-144 may contribute to AD pathogenesis by reducing ADAM10 activity, which ultimately resulting in increased Aβ production. This hypothesis was further confirmed by the fact that overexpression of miR-144 can downregulate the level of ADAM10 and inhibit the production of the Aβ [44].

Alternatively, in the amyloidogenic pathway, cleavage by the β-secretase cleaving enzyme 1 (BACE1) generates soluble AβPPβ (sAβPPβ), which is secreted, and a C-terminal fragment (β-CTF or c99). Subsequent cleavage of c99 by the γ-secretase complex generates Aβ and the AβPP intracellular domain (AICD), which can be further cleaved by caspases to produce a c31 fragment. BACE1 is a rate-limiting secretase that converts AβPP to Aβ [45 –48]. BACE1 levels are increased in AD patients and can raise the risk for sporadic AD [49, 50]. Studies have reported a relationship between abnormal miRNA expression and increased levels of BACE1 [51]. It has been reported that a significant decrease in miR-29a and miR-29b levels leads to an increased amount of BACE1. BACE1 is the target gene of miR-29b-1, and thus could serve a role in regulating BACE1 [52, 53]. Upregulation of BACE1 has been observed during postmortem analyses, though there is no change in the mRNA of BACE1 [33]. MiR-29c has been proposed as an endogenous BACE1 regulator [42]. In vitro, miR-29c leads to decreased expression of BACE1 protein; likewise, an overexpression of miR-29c in mice yields lower BACE1 concentrations [53]. More and more studies have shown that miR-107, miR-298, miR-328, miR-15a, miR-15b, miR-195, and miR-103 target the 3’UTR of BACE1. In AD patients, the levels of each of these miRNAs decrease [36–38 , 54–56]. Altogether these results suggest that miRNAs contribute to AD pathology via altering the BACE1 expression.

There also exists other ways by which microRNA affects AD pathology. For instance, decreased monocyte lysosomal hydrolases, including enzymes Cathepsin B, D, and S, also play a role in accumulation of Aβ [40]. New research shows that miR-128 upregulation is responsible for the downregulation of Cathepsin B, D, S, β-Galactosidase, α-Mannosidase, and β-Hexosaminidase [41].

Of note, although these miRNAs have been shown to have direct or indirect relationships with Aβ deposition, their regulatory mechanisms remain unknown. Further research is expected to yield more information on the subject.

Above we discuss the direct or indirect regulation of miRNAs on Aβ deposition; however, some other studies also showed downstream effects of Aβ on miRNA expression. Primary hippocampal neurons incubated with Aβ₄₂ showed a strong alteration in miRNA profiles with a substantial proportion of miRNAs being downregulated, including miR-9, miR-181c, miR-30c, miR-20b, and miR-361 [57].

This result was paralleled in animal model studies. In an AβPP/PS1 double mutant mouse model, several miRNAs (miR-20a, -29a, -125b, -128a, and -106b) were also downregulated. It seems that the miRNA network in AD is tightly regulated by feedback loops, Aβ production may lead to miRNA dysregulation, which in turn can affects AβPP mRNA levels and Aβ production.

miRNAs related to intraneuronal neurofibrillary tangles (NFT)

Abnormal accumulation of tau is another characteristic of AD. Tau is a protein that assembles and stabilizes microtubules. Tau is generated by neurons and accumulates in axons. Phosphorylation of tau is increased during the AD process to form p-tau and then form NFT [58]. MiR-128 regulates the production of a co-chaperone protein named BAG2, which takes part in the degradation and aggregation of tau [59]. MiR-124, miR-132, and miR-9 can change the accumulation of endogenous tau [60, 61]. Another study found that both miR-34a and miR-26b can inhibit tau expression, and thereby affect NFT formation [62]. Evidence showed that increasing miR-9 expression occurs concurrently with decrease of sirtuin (SIRT-1) which takes part in the pathology of tau as a deacetylase [63, 64]. Additionally, miR-34c has recently been found to affect SIRT-1 in AβPPS1-21 mouse [65]. Phosphorylation of tau is of great importance in AD process. A new study shows that down-regulation of miR-101 increases the level of phosphorylated tau [66]. A very recent study demonstrates that miR-922 binds to the 3’UTR of ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), leading to decreased the expression of UCHL1, which can reduce the level of phosphorylated tau [67]. These findings suggest that miRNAs could contribute to AD by altering the accumulation or phosphorylation of tau.

miRNA related to inflammation

Inflammatory responses are another characteristic of AD. Moderate responses can protect elderly people against cell damage, while excessive responses lead to neurodegeneration. Recent studies have confirmed that miRNAs can affect the inflammatory response in AD pathogenesis. Decreased expression of miR-101 leads to the upregulation of cyclooxygenase-2 (COX-2), an inflammatory factor [38]. Increasing levels of miR-146 can induce the inflammatory pathological response in AD by targeting specific genes. A close relationship has also been observed between IL-1 and miR-146. An increased level of miR-146a leads to the decrease of interleukin-1β-associated kinase-1 (IRAK-1) [68], which confirms that miR-146 functions in the inflammatory response. Further, at high levels miR-146a can combine with complement factor H (CFH) and interact with the 3’UTR of the factor to inhibit the inflammatory response [54, 69]. MiR-155, which features CFH binding sites that overlap with those of miR-146a, also has the same function. Increased levels of miR-125b, which is important in neuronal differentiation, have been correlated with glial cell proliferation and astrogliosis under inflammatory neurodegenerative conditions in AD [70 –72]. This miRNA further regulates the expression of D1, a potent neuroprotectin. Both the downregulation of SYN-2, a neuronal-enriched phosphoprotein related to the cytoplasmic surface of synaptic vesicles, and CFH are associated with miR-125b and inhibit the innate immune response [73].

miRNAs related to neuron death and axonal pathology

When detrimental stimulation occurs, cell death signaling pathways including necrosis, apoptosis, caspase-independent apoptosis, autophagy, and so on are activated. Apoptosis is one cause of cell death in the AD brain. In early stages of AD, neuronal death in the hippocampus may result from an apoptosis-inducing factor that acts as a scavenger of reactive oxygen species. This apoptosis-inducing factor can also trigger caspase-independent neuronal death [74]. Several miRNAs are known to regulate cell death in AD and many other neurodegenerative diseases. MiR-34, for example, inhibits the translation of bcl2, a protein related to caspase-3 [65]. MiR-15 also regulates levels of bcl-2 in AD [75]. By targeting BACE1, miR-124 impedes cell death in AD [76]. It has been showed that miR-342-5p can upregulate the expression of Ankyrin G (AnkG). AnkG is important to maintain the structure of the axon initial segment (AIS), cytoskeleton, and neuronal polarity. The down-regulation of AnkG could cause the impairment of AIS filtering and lead to abnormal trafficking of proteins. This can result in protein aggregation in the axon and impairment of axonal fast transport [77]. MiR-29a and miR-29b can lead to brain cell death by regulating DNA methyltransferases 3A and 3B [78]. All this suggested that MiRNAs can participate in the pathogenesis of AD by affecting neuronal apoptosis and axonal pathology.

DIAGNOSTIC POTENTIAL OF microRNA AS BIOMARKERS FOR AD

miRNAs as biomarkers

Although the use of imaging techniques has proven effective at early AD diagnosis, the available methods are still too late for implicating preventative measures. Further, during the progression of AD, serious morphological changes occur in the brain that can render pharmacological interventions ineffective [79, 80]. Thus, early diagnosis by means such as use of biomarkers is highly necessary to help prevent or better treat the disease. Recent biomarker technologies mainly focus on genomics, neuroimaging, epigenomics, transcriptome metabolomics, lipidomics, and proteomics, and also miRNAs [81 –83]. Compared with protein-based biomarkers, miRNAs can cross the blood-brain barrier. Although miRNAs have a short half-life, miRNAs could exist for a long time because of the protection of exosome membranes and other microparticles in body fluids, such as CSF, blood, urine, saliva, and milk [84, 85]. Importantly, unlike many biomarkers in CSF, the abnormal expressions of miRNAs happens prior to passing into the CSF, thus, they would be an effective diagnostic indicator. Concurrently, the approaches to detect the miRNA biomarkers are more convenient and cheaper for monitoring large populations. Considering all these advantages, miRNAs have great potential as biomarkers for AD diagnosis.

Diagnostic methods using miRNAs

Altered miRNAs in body fluids, including CSF and blood, are associated with the pathomechanism of AD, such as Aβ deposition and cell death. Hence, disease progression can be monitored by examining disease-related miRNAs. Three approaches are actively used for analysis of miRNA as potential biomarkers.

(i) Examining miRNAs through arrays or next-generation sequencing [86].

We can effectively find potential biomarkers by analyzing vast amount of variable miRNAs and detecting miRNA sequence variation [87]. However, there are three obvious disadvantages. First, they cannot detect miRNAs at the low concentrations in body fluids. Second, the source of miRNAs identified by this method is ubiquitous, which means it cannot be determined whether the miRNAs come from other tissues or blood cells. Third, altered miRNAs have low specificity toward AD, meaning changes may also be observed and indicative of other diseases, such as cancer, hypoxia, and so on [88].

(ii) Identifying disease-specific miRNAs.

Contrasting miRNAs isolated from pathological and normal tissues can help to determine disease-specific miRNAs. Arrays or RT-PCR can then help identify these miRNAs in body fluids [89, 90]. This method largely reduces the number of miRNAs tested, increases sensitivity and reproducibility, and is suitable for detecting CSF-originating miRNAs because the CSF is connected to brain and few miRNAs may be obtained from other organs. However, the advantages of this technique are negligible when searching for biomarkers in blood. Alterations caused by pathology occur to some extent in blood and other changes may dilute or even contort these alterations [32].

(iii) Analyzing circulating brain-enriched miRNAs in body fluids.

This approach was proposed for searching biomarkers for AD and other neurodegenerative diseases. RT-PCR is used to measure miRNAs that are either enriched in the disease-related brain area, for example in the hippocampus for AD, or present in disease-related neurites and synapses. By simply measuring brain-enriched miRNAs, detecting changes caused by disease becomes much easier. Further, brain-enriched miRNAs at levels too low to be detected by arrays can be detected by RT-PCR [84, 91].

Finding effective miRNA normalizations is very important in determining disease-related miRNA alterations in body fluids as many biological and technical factors influence miRNA levels. These factors include miRNA concentrations in the plasma that have been affected by miRNAs from various organs, tissues, and cells; blood-brain barrier permeability for brain-enriched miRNAs; miRNA stability in the plasma and their different appearances (e.g., exosomes and other micro-vesicles); and complexes with proteins, lipids, and other molecules. Technical factors include methods for bodily fluid collection and storage, miRNA extraction, and other conditions affecting miRNA purification and RT-PCR [92].

Methods for normalizing circulating miRNA are available, including normalization per spiked miRNA, normalization per ubiquitous and the least-variable circulating miRNA, normalization per other small RNA, and so on [93 –97]. The method called “miRNA pairs” has recently been used in several investigations. A miRNA pair consists of two plasma miRNAs with common properties, including secretion or excretion by the same mechanism, binding to the same protein in plasma, appearance in similar exosomes, and distinct alterations in the same pathology. This approach can obviously increase sensitivity and specificity while avoiding potential overlaps with the pathologies of other organs.

For neurodegenerative diseases, neurite/synapse miRNA can be combined with a neuronal body miRNA to monitor disease progress from synapse destruction to neuronal death. A pathological process may change some or all of the factors. To expect that the numerator and denominator of an effective biomarker miRNA pair will share some of these basic factors (e.g., both are brain-enriched and secreted in exosomes), and then change differently in response to certain pathology, is logical. Although this analytical method covers a large number of miRNA and has, several advantages over other methods, low sensitivity and high variability may be obtained. However, it is still favorable over analysis of cell-free miRNA in plasma or serum. This is not advisable because the sum of miRNAs in plasma is low and the dramatic changes in miRNA levels cannot be expected to yield trusted results for a chronic pathology [89, 98, 99 , 89, 98, 99].

miRNA in blood and CSF

Considering the prospective use of miRNAs as biomarkers, many studies have concentrated on finding miRNA-based biomarkers in the CSF and blood for AD diagnosis [100]. Geekiyanage et al. found that ceramide can accelerate mislocation of BACE1 and γ-secretase and facilitate production of Aβ. Serine palmitoyle transferase (SPF), the rate-limiting enzyme in the de novo synthesis of ceramide [101], is post-transcriptionally regulated by miR-137/-181c and miR-9/-29a/b. Decreases in miR-137, miR-181c, miR-9, and miR-29a/b-1 correlate with increases in SPF and, in turn, Aβ production [55]. This phenomenon shows variations are based on gender [102]. The extent of decrease in miR-137, miR-181c, and miR-29a/b-1 is larger among female patients than among male patients [55]. This result indicates that miRNAs may be markers of AD diagnosis. Later studies prove that when compared with age-matched normal controls, miRNA levels in the blood serum of AD patients and AD risk factor models will both decrease.

A study recently examined the concentrations of six miRNAs candidates, including miR-9, miR29a, miR-29b, miR-34a, miR-125, and miR-146a, in the CSF and plasma of AD patients and age-matched controls [103, 104]. All of these miRNAs has been showed to have important functions in the CNS and the pathology of AD. AD patients had increased levels of miR-34a in the brain and decreased levels of the miRNA in CSF and plasma [105]. This indicates that miR-34a cannot be secreted from the brain to the CSF or plasma, and that it may promote AD pathogenesis. Further, miR-34a can interact with Bcl-2, which prevents caspase-9 activation [106]. MiR-34c, a sister of miR-34a, was increased in both the peripheral blood mononuclear cells and plasma of patients [107]. MiR-34c, like the miR-34a, can repress SIRT-1 and Bcl-2 expression and then cause the dysregulation of oxidative defense and cell survival in AD patients [66]. Compared with levels in the AD brains, miR-29a [108] and miR-29b [103] increase in the CSF and remain unchanged in plasma. This outcome suggests that miR-29a and miR-29b in the CSF originate from the brain.

Both miR-125 and miR-9 are brain-rich miRNAs. Levels of miR-125 and miR-9 decreased in the CSF and plasma, respectively, and showed no change, which indicates that these two miRNAs have different paths from the brain to the CSF and plasma [103, 109]. By analyzing expression of cell-free miRNAs in both the CSF and the serum, a study demonstrated that miR-125b can be a biomarker for AD with an accuracy of 82% [110]. The increasing level of miR-27a can help to distinguish AD patients from unaffected people, and MiR-27a also correlated with CSF tau and Aβ levels [111]. Altogether, these miRNAs described above has the potential to be biomarkers for early diagnosis of AD.

Neurite and synapse destruction occur in the early stages of AD followed by neuron loss [112]. Sheinerman et al. investigated several neuron-rich and neurite/synapse-involved miRNAs collected from plasma. Mentioned above “miRNA pair” approach was used for data normalization. Finally, two miRNA pairs were identified [84, 91]: the miR-132 family (miR-128/miR-491-5p, miR-132/miR-491-5p, and mir-874/miR-491-5p) and the miR-134 family (miR-134/miR-370, miR-323-3p/miR-370, and miR-382/miR-370). Variations in these miRNAs levels can be applied to distinguish mild cognitive impairment from age-matched controls 1–5 years before clinical diagnosis. However, mild cognitive impairment cannot be differentiated from AD on the basis of these miRNAs, though the specificity and sensitivity of the miRNA pairs are higher than those of individual miR-132 or miR-134 family biomarkers. The two have been shown to have opposite functions. MiR-132 stimulates neurite growth whereas miR-134 impedes it [113 –115]. Meanwhile, a study found that the upregulation of miR-134 is also combined with aging [116]. This study confirms the assumption that miRNA pairs, especially neurite/synapse miRNAs, may be applicable for the early diagnosis of AD as dysfunctions of the synapse and destruction of neurites/synapses are early events of AD. A recent study analyzed miRNA concentrations in the CSF and brain tissue-derived, extracellular fluid of AD patients. It revealed that concentrations of miRNA-9, miRNA-125b, miRNA-146a, and miRNA-155 are increased in the CSF and extracellular fluid of AD patient [117]. Previous studies have also demonstrated that these four miRNAs regulate innate immune and inflammatory responses and correlate with NF-κB levels [118]. These findings indicate that AD can be diagnosed by investigating disease-related miRNAs/miRNA pairs.

PERSPECTIVE

AD pathology usually arises decades before the clinical diagnosis is effectively made; therefore early detection of AD has become one of the principal focuses of research nowadays. The available methods such as imaging techniques are too late for implicating preventative measures, thus, establishment of early diagnosis by other means, such as use of biomarkers, is highly necessary to help prevent or better treat the disease. Our knowledge of microRNAs has been greatly improved in recent years and the implications of miRNA in AD offer a new approach to elucidate underlying molecular mechanisms in AD progress as well as to discover potential diagnostic biomarkers [119]. Actually, circulating miRNAs have been proposed as one of the most promising biomarkers for AD as well as other neurodegenerative diseases.

Despite the increasing number of studies being conducted on the diagnostic applications of miRNAs, applying miRNAs to screen AD or other central nervous system diseases remains elusive. As discrepancies between different studies, normalizations, and miRNA detection methods have been discussed here, further studies are needed to find a uniform process for studying miRNAs as diagnostic biomarkers.

On the other hand, the functions of several miRNAs in AD and other diseases have been elucidated, but many subjects are still under investigation, such as the complementary roles of specific transcription factors, the specific targets of pathogenic miRNAs in AD, and the selective involvement of miRNAs in different regions of the brain. Only through extensive study can the effects of miRNAs on the initiation and progression of AD be determined.

In summary, AD is a complicated CNS disease and the main cause of dementia among the elderly. Techniques, such as MRI and X-rays, can only detect the late stages of AD, during which irreversible damage has likely occurred. Studies on miRNAs in AD not only help explain the pathogenesis of AD but also may enable early-stage diagnosis and treatment of AD. MicroRNAs have a great potential as biomarkers in diagnosis, involving in progression of AD and other neurodegenerative diseases. A better understanding the role of microRNA in physiological and pathological conditions is of great importance to validate their use as non-invasive biomarkers.

Footnotes

ACKNOWLEDGMENTS

This work was supported by the National Natural Science Foundation of China (No. 31372407), and Henan Scientific and technological project (No. 132102110118).

Authors’ disclosures available online ().

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