MicroRNAs as a Diagnostic Biomarker in Alzheimer’s Disease: Potential Roles and Characteristics
Chang Youn Lee1, Jin Hyeob Ryu1* and Hyun Jeong Cho2*
1Biorchestra Co. Ltd., Techno 4-ro, 17, Daejeon 34013, South Korea
2Department of Biomedical Laboratory Science, College of Medical Science, Konyang University, 158, Gwanjeodong-ro, Seo-gu, Daejeon 35365, South Korea
Submission: September 2, 2021; Published: September 14, 2021
*Corresponding author: Jin-Hyeob Ryu, Biorchestra Co. Ltd., Techno 4-ro, 17, Daejeon 34013, South Korea, e-mail: jhyeup@gmail.com
Hyun-Jeong Cho, Department of Biomedical Laboratory Science, College of Medical Science, Konyang University, 158, Gwanjeodong-ro, Seo-gu, Daejeon 35365, South Korea, e-mail: hjcho@konyang.ac.kr
How to cite this article: Chang Y L, Jin H R, Hyun J C. MicroRNAs as a Diagnostic Biomarker in Alzheimer’s Disease: Potential Roles and Characteristics. Glob J Intellect Dev Disabil, 2021; 9(1): 555753. DOI:10.19080/GJIDD.2021.09.555753
Abstract
As the world moves towards an aging society, it faces enormous public health challenges. Among them, an increased number of patients with dementia poses a serious socioeconomic burden. Alzheimer’s disease (AD) is the most important type of dementia and despite many studies, cannot be cured by modern medicine. However, the progression of the disease can be delayed; therefore, early diagnosis of AD is very important. MicroRNAs (miRNAs) are abundant in the CNS, and their profiles get altered in degenerative brain diseases. Studies analyzing the tissues, blood, and cerebrospinal fluid of AD patients have shown an up-regulation in some miRNA expression and a decrease in some miRNAs. These miRNAs are involved in modulating the production of amyloid beta, hyperphosphorylation of tau protein, and synaptic plasticity. These characteristics make miRNAs very attractive tools for disease diagnosis. Through this review, we intend to investigate the characteristics and vulnerabilities of miRNAs in AD diagnosis.
Keywords: Alzheimer’s disease; Diagnosis; Biomarker; miRNA
Abbreviations: AD: Alzheimer’s Disease; miRNA: microRNA; CSF: Cerebrospinal Fluid; SIRT1: Silent Information Regulator Transcript-1; NAV3: Neuron Navigator 3; BDNF: Brain-Derived Neurotrophic Factor; CDK5: Cyclin-Dependent Kinase 5
Introduction
The world is becoming an aging society, and it faces enormous challenges to public health. One of them is the increase in patients with dementia, which is a huge socio-economic burden. Alzheimer’s disease (AD) is a complex neurodegenerative disease and is the most usual brain disease that causes dementia [1]. According to some reports, 10% of the population aged 65 years and older is affected by AD, and the incidence nearly doubles every 5 years [2]. This phenomenon occurs in both developed and developing countries [2].
AD usually progresses gradually, leading to cognitive impairment and memory loss. The pathological features of AD include the formation of amyloid plaques and neurofibrillary tangles caused by amyloid-β metabolism and hyperphosphorylation of tau protein, respectively [3,4]. In addition, AD shows loss of neuroplasticity and inflammatory responses [5,6]. Although the causes of AD have already been discovered, it is considered as an incurable disease in modern medicine [6]. However, early diagnosis can enable the delay of disease progression, and therefore, it becomes critical in dealing with AD patients.
MicroRNAs (miRNAs) are small non-coding RNAs that bind to complementary sequences (seed sequence) on the target RNA and regulate post-transcriptional gene expression [7]. miRNAs are abundant in the CNS and are closely involved in neural development [8,9], neuronal differentiation [10,11], and synaptic plasticity [12,13]. Studies have shown that miRNA expression is altered in neurodegenerative diseases such as AD [14,15]. In addition, several miRNAs have been identified as critical regulators in the pathogenesis of AD [16]. Based on these characteristics, miRNAs are gaining attention as promising biomarkers for the diagnosis of AD [17,18]. In this review, we have shown evidence regarding the potential of miRNAs for AD diagnosis.
Discussion: miRNA as diagnostic AD Biomarker Candidates
Increased miRNAs in AD
Studies have shown that miRNAs regulate Aβ metabolism. Gaurav et al. [19] identified miRNAs, such as miR-27a-3p, miR- 30a-5p, and miR-34c, as biomarkers for ADs and reported that these miRNAs get increased in patients with AD [19]. These miRNAs have been shown to play roles in memory function and neurodegeneration in previous studies.
Yu et al. [20] revealed that miR-485-3p can be used as a biomarker and therapeutic target of AD, as they found increased miR-485-3p expression level in the serum of AD patients. In addition, they showed that miR-485-3p affects neuroinflammation by targeting AKT3 [20].
Studies have shown increased expression of miR-34 family in patients with AD [21,22]. MiR-34 is involved in neuronal synaptic deficiency, resting-state network activity, and energy metabolism [19,21]. Sarkar et al. [21] reported that miR-34, by inhibiting SIRT, increases Aβ production in AD patients [21]. In addition, Shephali et al. [22] reported that the expression of miR-34a, miR-34b, and miR-34c is increased in the plasma of AD patients, with miR-34c showing a significantly increased level in patients with sporadic AD [22].
Increased expression of the miR-200 family has been reported in previous studies [23, 24]. Zhang et al. [23] reported that miR-200a-3p upregulates Aβ-induced neuronal apoptosis by inhibiting the silent information regulator transcript-1 (SIRT1) in APP/PSEN1 mice [23]. In addition, Higaki et al. [24] reported that expression of the miR-200 family (miR-200a, -141, -429, -200b, -200c) is increased in the initial phases of AD. Moreover, this study showed that miR-200b/c increases Aβ accumulation in Tg2576 transgenic mice by regulating insulin signaling [24].
MiR-146a is increased in the brains of patients with AD and is involved in neuroinflammation and aging [25,26]. Dysregulation of miR-146a causes abnormal tau hyperphosphorylation and Aβ deposition in patients with AD. Li et al. [27] reported that miR- 146a promotes amyloidogenesis by regulating the expression of IRAK1, TRAF6, TSPAN12 (tetraspanin12), and ADAM10 [27]. Wang et al. [28] further revealed that inhibition of miR-146a suppresses hyperphosphorylation and restores memory function by suppressing ROCK1 in 5x FAD mice [28].
Studies have now shown that miRNAs can also regulate abnormal phosphorylation of tau in AD patients. MiR-125b is up-regulated in AD patients, which induces apoptosis and hyperphosphorylation of tau in AD patients [29,30]. Ma et al. [29] found that miR-125b induces neuronal cell death and abnormal tau phosphorylation by regulating cyclin-dependent kinase 5 (CDK5) and p35/25 [29]. Banzhaf-Strathmann et al. [30] showed similar results where miR-125b affects tau phosphorylation by regulating p35, CKD5, and MAPK signaling in AD. Moreover, these authors showed that increased miR-125 impairs learning and memory, induces neurotoxicity, and expedites AD progression in patients [30].
MiR-206 is elevated in the brains of AD patients [31,32]. Moon et al. [31] reported that miR-206 levels were increased specifically in patients with olfactory mucosal AD. The study suggested that memory impairment in patients is caused by decreased expression of brain-derived neurotrophic factor (BDNF) by miR- 206. Moreover, the study suggested that miR-206 has the potential to be used as an early diagnostic marker of AD. Kenny et al. [32] also reported that miR-206 is increased in the plasma of patients with AD. They suggested that the measurement of change in miR- 206 expression in plasma may be used to predict cognitive decline and memory loss [32].
Decreased miRNAs in AD
miRNAs control key physiological parameters, such as the number and strength of synaptic inputs and intrinsic excitability, to maintain homeostatic plasticity [39]. However, alterations in miRNA expression that are caused by the pathological environment may contribute to disease progression as well as homeostatic failure.
In a 2008 report by Wang et al. [33] 70 miRNAs were selected through miRNA array analysis using brain tissues from early AD, severe AD, and control groups [33]. Among them, miR-107 was significantly reduced in the early stages of AD. miR-107 binds to BACE1 mRNA 3UTP and inhibits β-secretase1 expression. Therefore, decreased miR-107 expression in patients with early-stage AD is closely related to Aβ production by increased β-secretase1 levels.
In addition, it has been reported that miR-29a is significantly reduced in brain tissue obtained from patients with degenerative brain disease. This study revealed that miR-29a targets neuron navigator 3 (NAV3), whose expression was increased in degenerating pyramidal neurons in the cerebral cortex of patients with AD. These results revealed that the reduction of miR-29a expression promotes neurodegenerative diseases by enhancing NAV3 expression in neurons [34].
In a 2017 report, Haea et al. [35] investigated miRNAs in the serum of 45 people (control group: 18 people, AD group: 27 people), and found that the expression of miR-501-3p was reduced in the AD group. Consequently, a significant correlation was established using the Mini-Mental State Examination score. In addition, overexpression of miR-501-3p in cells revealed that miR-501-3p was able to suppress 128 genes regulating DNA replication and mitosis. Therefore, the reduced expression of miR- 501-3p could be used as a biomarker for AD diagnosis [35].
In addition, some studies revealed that the levels of miR-34a and miR-146a in plasma and miR-34a, miR-125b, and miR-146a in cerebrospinal fluid (CSF) were significantly reduced in AD patients compared to controls [21,37]. As such, miRNAs that are significantly down-regulatd in AD patients have the potential to be developed as new biomarkers for AD diagnosis (Table 1).
Conclusion
miRNAs are powerful molecules for the evaluation of clinical samples. Recent studies have suggested their novel potential as a diagnostic biomarker of cancer [40,41], obesity [42,43], brain disease [44,45], and heart disease [46-49]. However, using miRNAs for clinical applications still poses challenges that need to be solved. First, miRNAs are single-stranded small RNA molecules and can be quite unstable depending on the sampling method and sample storage environment [50]. Second, some miRNAs may have different profiles in the tissues, blood, and CSF [51]. Therefore, clear criteria for sampling and sufficient evidence for miRNA selection are required. Third, non-standardized RNA extraction methods and variability in analysis may cause confusion in the interpretation of results [52,53]. Lastly, evidence regarding miRNAs as biomarkers has not yet been sufficiently reported. Although miRNAs are very attractive as biomarkers, there is insufficient evidence to overcome their limitations, which is required for the development of more reliable diagnostic technologies. In the future, if more research is conducted and miRNA detection and analysis methods are standardized, it will lead to the development of new biomarkers.
Acknowledgement
We would like to thank all participants.
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