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.

Keywords: APOE; Alzheimer’s disease; amyloid precursor protein; beta-amyloid; diagnosis; microRNA; neuroinflammation; tau; therapy.

Figure 1

A summary of miRNAs directly targeting MAPT transcripts and related kinases, including GSK-3β, CDK5, DYRK1A, and DAPK1.

Figure 2

A summary of miRNAs directly targeting APP transcripts, BACE1 transcripts, and related kinases, including GSK-3β, CDK5, JNK, and DAPK1.