MicroRNA-298 reduces levels of human amyloid-β precursor protein (APP), β-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties

Nipun Chopra, Ruizhi Wang, Bryan Maloney, Kwangsik Nho, John S. Beck, Naemeh Pourshafie, Alexander Niculescu, Andrew J. Saykin, Carlo Rinaldi, Scott E. Counts, Debomoy K. Lahiri

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Alzheimer’s disease (AD) is the most common age-related form of dementia, associated with deposition of intracellular neuronal tangles consisting primarily of hyperphosphorylated microtubule-associated protein tau (p-tau) and extracellular plaques primarily comprising amyloid- β (Aβ) peptide. The p-tau tangle unit is a posttranslational modification of normal tau protein. Aβ is a neurotoxic peptide excised from the amyloid-β precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. MicroRNAs (miRNAs) are short, single-stranded RNAs that modulate protein expression as part of the RNA-induced silencing complex (RISC). We identified miR-298 as a repressor of APP, BACE1, and the two primary forms of Aβ (Aβ40 and Aβ42) in a primary human cell culture model. Further, we discovered a novel effect of miR-298 on posttranslational levels of two specific tau moieties. Notably, miR-298 significantly reduced levels of ~55 and 50 kDa forms of the tau protein without significant alterations of total tau or other forms. In vivo overexpression of human miR-298 resulted in nonsignificant reduction of APP, BACE1, and tau in mice. Moreover, we identified two miR-298 SNPs associated with higher cerebrospinal fluid (CSF) p-tau and lower CSF Aβ42 levels in a cohort of human AD patients. Finally, levels of miR-298 varied in postmortem human temporal lobe between AD patients and age-matched non-AD controls. Our results suggest that miR-298 may be a suitable target for AD therapy.

Original languageEnglish (US)
JournalMolecular Psychiatry
DOIs
StateAccepted/In press - 2020

ASJC Scopus subject areas

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

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