MicroRNAs as Potential Orchestrators of Alzheimer's Disease-Related Pathologies: Insights on Current Status and Future Possibilities

Abstract

Alzheimer's disease (AD) is a progressive and deleterious neurodegenerative disease, strongly affecting the cognitive functions and memory of seniors worldwide. Around 58% of the affected patients live in low and middle-income countries, with estimates of increasing deaths caused by AD in the coming decade. AD is a multifactor pathology. Mitochondrial function declines in AD brain and is currently emerging as a hallmark of this disease. It has been considered as one of the intracellular processes severely compromised in AD. Many mitochondrial parameters decline already during aging; mitochondrial efficiency for energy production, reactive oxygen species (ROS) metabolism and the de novo synthesis of pyrimidines, to reach an extensive functional failure, concomitant with the onset of neurodegenerative conditions. Besides its impact on cognitive functions, AD is characterized by loss of synapses, extracellular amyloid plaques composed of the amyloid-β peptide (Aβ), and intracellular aggregates of hyperphosphorylated Tau protein, accompanied by drastic sleep disorders, sensory function alterations and pain sensitization. Unfortunately, till date, effective management of AD-related disorders and early, non-invasive AD diagnostic markers are yet to be found. MicroRNAs (miRNAs) are small non-coding nucleic acids that regulate key signaling pathway(s) in various disease conditions. About 70% of experimentally detectable miRNAs are expressed in the brain where they regulate neurite outgrowth, dendritic spine morphology, and synaptic plasticity. Increasing studies suggest that miRNAs are intimately involved in synaptic function and specific signals during memory formation. This has been the pivotal key for considering miRNAs crucial molecules to be studied in AD. MicroRNAs dysfunctions are increasingly acknowledged as a pivotal contributor in AD via deregulating genes involved in AD pathogenesis. Moreover, miRNAs have been proved to control pain sensitization processes and regulate circadian clock system that affects the sleep process. Interestingly, the differential expression of miRNA panels implies their emerging potential as diagnostic AD biomarkers. In this review, we will present an updated analysis of miRNAs role in regulating signaling processes that are involved in AD-related pathologies. We will discuss the current challenges against wider use of miRNAs and the future promising capabilities of miRNAs as diagnostic and therapeutic means for better management of AD.

miR-143-3p Inhibits Aberrant Tau Phosphorylation and Amyloidogenic Processing of APP by Directly Targeting DAPK1 in Alzheimer’s Disease

“…Because the DAPK1 levels are aberrantly elevated in patients with AD [ 10 , 11 , 16 ], we first investigated the molecular mechanisms regulating DAPK1 expression. MiRNAs have been extensively studied as critical post-transcriptional regulatory factors of gene expression and show promise for the diagnosis and treatment of AD [ 28 , 30 , 31 ]. To determine the potential modulation of DAPK1 expression by miRNAs, we employed bioinformatics databases to predict potential miRNA candidates targeting the 3′ untranslated region (3′UTR) of DAPK1 mRNA.…”

“…Insights into the roles of miRNAs in numerous diseases, including cancer, cardiovascular diseases, and neurological diseases, have contributed to the development of miRNA-based therapeutic strategies [ 25 , 26 ]. Up to 70% of miRNAs are found in the human brain and play important roles in AD-related pathologies [ 27 , 28 , 29 ]. Recent studies have found that miRNA replacement therapies rescue adult hippocampal neurogenesis and memory deficits in AD models [ 30 ].…”

“…Recent studies have found that miRNA replacement therapies rescue adult hippocampal neurogenesis and memory deficits in AD models [ 30 ]. To date, miRNAs have shown diagnostic and therapeutic value in AD [ 28 , 31 ]. Whether miRNAs regulate tau phosphorylation and APP processing through DAPK1 remains unknown.…”

Biomarkers of Frailty: miRNAs as Common Signatures of Impairment in Cognitive and Physical Domains

“…Actually, it is known that the brain expresses about 70% of experimentally detectable miRNAs [ 155 ].…”

MicroRNA-Target Interaction Regulatory Network in Alzheimer’s Disease

“…Potential therapeutic approaches are, however, not limited to AM strategies. Studies on cell cultures and animal models have also identified compounds that affect miRNA expression [22]. Current commonly used diagnostic methods are primarily based on CSF biomarkers.…”