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

Nermeen Z Abuelezz,Amira Zaky,Mohammad Ahmed Abdulkader,Fayza Eid Nasr,Ahmad R Bassiouny

doi:10.3389/fnagi.2021.743573

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.

Highlights

Alzheimer’s: A Peculiar Case of BrainDisease “Alois Alzheimer,” The German Bavarian psychiatrist, and neurologist was the first to report Alzheimer’s disease (AD) in 1906 as “A peculiar severe disease of the cerebral cortex” (Hippius and Neundörfer, 2003)
In vitro and in vivo studies show that downregulation of miR-137 determines an increase in Ca2+ levels and a reduction of Aβ1-40 and Aβ1-42. These results indicate that an increase in miR-137 could cause a decrease in Ca2+ levels in neurons, improving neuronal dysfunctions of AD (Davare and Hell, 2003)
One interesting point is that along our research, numerous miRNAs apparently act as multi-faceted modulators of ADinterconnected signaling pathways

Summary

Introduction

Alzheimer’s: A Peculiar Case of BrainDisease “Alois Alzheimer,” The German Bavarian psychiatrist, and neurologist was the first to report Alzheimer’s disease (AD) in 1906 as “A peculiar severe disease of the cerebral cortex” (Hippius and Neundörfer, 2003). The loss of neuronal connections in AD brain is basically attributed to disrupted signaling pathways that affect both synaptic plasticity and dendritic functions, the two crucial controllers of cognitive processes.

Results

Conclusion