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Updated: Jun 30, 2026

Harnessing the Power of MicroRNA Cargoes in Small Extracellular Vesicles Released from Fresh-Frozen Human Brain Sections
07:55

Harnessing the Power of MicroRNA Cargoes in Small Extracellular Vesicles Released from Fresh-Frozen Human Brain Sections

Published on: November 8, 2024

MicroRNA-181 influences Alzheimer's risk by regulating neprilysin and microtubule-associated tau pathways, offering a

Ruizhi Wang1, Bryan Maloney1, Kwangsik Nho2

  • 1Laboratory of Molecular Neurogenetics, Departments of Psychiatry, Stark Neuroscience Research Institute, Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA.

Biorxiv : the Preprint Server for Biology
|June 29, 2026
PubMed

Insights

MicroRNA-181d-5p (miR-181d) is linked to Alzheimer's disease (AD) risk. It influences neprilysin and tau proteins, potentially offering new therapeutic targets for AD.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Alzheimer's disease (AD) involves amyloid-β (Aβ) plaques and tau tangles, but the link between these pathologies is unclear.
  • MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and are implicated in neurodegenerative diseases.
  • Understanding the role of specific miRNAs in AD pathogenesis is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the association of microRNA-181d-5p (miR-181d) with Alzheimer's disease (AD)-related brain changes.
  • To determine if miR-181d regulates neprilysin (NEP) and tau pathology, key factors in AD.
  • To identify novel molecular targets for AD intervention.

Main Methods:

  • Computational modeling of miR-181d levels in individuals with varying cognitive status (cognitively normal, mild cognitive impairment, AD).
  • Analysis of region- and sex-specific associations between miR-181d and AD probability.
  • In vitro cellular experiments to assess miR-181d's effect on neprilysin and tau expression and activity.
  • RNA sequencing to identify miR-181d-responsive pathways.

Main Results:

  • miR-181d levels showed region- and sex-specific associations with AD probability, notably in the temporal lobe, cerebellum, and posterior cingulate cortex.
  • Single nucleotide polymorphisms (SNPs) near MIR181 correlated with altered entorhinal cortical thickness.
  • In cellular models, miR-181d reduced neprilysin activity and increased tau mRNA and protein levels.
  • RNA sequencing revealed miR-181d-modulated neurodegenerative pathways.

Conclusions:

  • miR-181d is a significant regulator of both amyloid and tau pathways implicated in Alzheimer's disease.
  • The observed effects of miR-181d on neprilysin and tau suggest a mechanism linking amyloid clearance and tau pathology.
  • miR-181d and its downstream targets represent potential novel therapeutic targets for Alzheimer's disease.
Keywords:
AgingSNPsUTRamyloiddementiagenetic variantsmicroRNAneprilysintau

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