Human microRNA (miR-20b-5p) modulates Alzheimer’s disease pathways and neuronal function, and a specific polymorphism close to the MIR20B gene influences Alzheimer’s biomarkers

Ruizhi Wang, Nipun Chopra, Kwangsik Nho, Bryan Maloney, Alexander G. Obukhov, Peter T. Nelson, Scott E. Counts, Debomoy K. Lahiri

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with loss of cognitive, executive, and other mental functions, and is the most common form of age-related dementia. Amyloid-β peptide (Aβ) contributes to the etiology and progression of the disease. Aβ is derived from the amyloid-β precursor protein (APP). Multiple microRNA (miRNA) species are also implicated in AD. We report that human hsa-miR20b-5p (miR-20b), produced from the MIR20B gene on Chromosome X, may play complex roles in AD pathogenesis, including Aβ regulation. Specifically, miR-20b-5p miRNA levels were altered in association with disease progression in three regions of the human brain: temporal neocortex, cerebellum, and posterior cingulate cortex. In cultured human neuronal cells, miR-20b-5p treatment interfered with calcium homeostasis, neurite outgrowth, and branchpoints. A single-nucleotide polymorphism (SNP) upstream of the MIR20B gene (rs13897515) associated with differences in levels of cerebrospinal fluid (CSF) Aβ1-42 and thickness of the entorhinal cortex. We located a miR-20b-5p binding site in the APP mRNA 3′-untranslated region (UTR), and treatment with miR-20b-5p reduced APP mRNA and protein levels. Network analysis of protein-protein interactions and gene coexpression revealed other important potential miR-20b-5p targets among AD-related proteins/genes. MiR-20b-5p, a miRNA that downregulated APP, was paradoxically associated with an increased risk for AD. However, miR-20b-5p also reduced, and the blockade of APP by siRNA likewise reduced calcium influx. As APP plays vital roles in neuronal health and does not exist solely to be the source of “pathogenic” Aβ, the molecular etiology of AD is likely to not just be a disease of “excess” but a disruption of delicate homeostasis.

Original languageEnglish
Pages (from-to)1256-1273
Number of pages18
JournalMolecular Psychiatry
Volume27
Issue number2
DOIs
StatePublished - Feb 2022

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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