Potential Implications of miRNAs in the Pathogenesis, Diagnosis, and Therapeutics of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a complex multifactorial disorder that poses a substantial burden on patients, caregivers, and society. Considering the increased aging population and life expectancy, the incidence of AD will continue to rise in the following decades. However, the molecular pathogenesis of AD remains controversial, superior blood-based biomarker candidates for early diagnosis are still lacking, and effective therapeutics to halt or slow disease progression are urgently needed. As powerful genetic regulators, microRNAs (miRNAs) are receiving increasing attention due to their implications in the initiation, development, and theranostics of various diseases, including AD. In this review, we summarize miRNAs that directly target microtubule-associated protein tau (MAPT), amyloid precursor protein (APP), and β-site APP-cleaving enzyme 1 (BACE1) transcripts and regulate the alternative splicing of tau and APP. We also discuss related kinases, such as glycogen synthase kinase (GSK)-3β, cyclin-dependent kinase 5 (CDK5), and death-associated protein kinase 1 (DAPK1), as well as apolipoprotein E, that are directly targeted by miRNAs to control tau phosphorylation and amyloidogenic APP processing leading to Aβ pathologies. Moreover, there is evidence of miRNA-mediated modulation of inflammation. Furthermore, circulating miRNAs in the serum or plasma of AD patients as noninvasive biomarkers with diagnostic potential are reviewed. In addition, miRNA-based therapeutics optimized with nanocarriers or exosomes as potential options for AD treatment are discussed.

Mesenchymal Stem Cells from Familial Alzheimer’s Patients Express MicroRNA Differently

“…This alteration has a notable effect on the development of various neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) [36]. In AD, miRNAs in serum, cerebrospinal fluid, and brain tissue, as well as in transgenic models, have been studied [37][38][39][40][41]. Few studies have reported miRNAs in the early stages or related to the progression of AD [22,[41][42][43][44][45][46].…”

The six brain‐specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes

“…67 Muscleblind-like (MBNL) proteins are involved in developmental splicing and could potentially influence MAPT splicing, although direct evidence remains sparse. 68,69 71,72 ).…”

“…These miRNAs can indirectly regulate the expression of exon 10 trans ‐acting factors, thereby affecting the balance between 3R and 4R TAU isoforms. While the specific mechanisms by which these miRNAs regulate MAPT alternative splicing are still being elucidated, it is clear that miRNAs play a significant role in modulating the splicing of TAU pre‐mRNA, particularly in the context of tauopathies (reviewed in 71 , 72 ).…”

“…For the technical and molecular mechanism of MAPT alternative splicing, we refer the interested reader to recent exhaustive reviews (for example 33 , 50 , 68 , 70 , 71 , 72 , 73 , 74 , 75 ).…”

Implications in Cancer of Nuclear Micro RNAs, Long Non-Coding RNAs, and Circular RNAs Bound by PRC2 and FUS

“…Currently, the miRBase database ( ; accessed in 1 December 2023) lists over 2588 distinct miRNAs that are involved in nearly every cellular process, highlighting the vast and complex nature of this field of study [ 7 , 8 ]. Moreover, alterations in miRNA expression have been implicated in a myriad of diseases, emphasizing their importance in maintaining cellular homeostasis [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ].…”