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MicroRNA-125b induces tau hyperphosphorylation and cognitive deficits in Alzheimer's disease

Julia Banzhaf-Strathmann1, Eva Benito2, Stephanie May3

  • 1German Center for Neurodegenerative Diseases, Munich, Germany julia.banzhaf@dzne.lmu.de dieter.edbauer@dzne.de.

The EMBO Journal
|July 9, 2014
PubMed

Insights

MicroRNA-125b (miR-125b) promotes Alzheimer's disease (AD) by increasing tau phosphorylation. Lowering miR-125b levels may offer a therapeutic strategy for AD by reducing pathological tau accumulation.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Sporadic Alzheimer's disease (AD) is the most common form of dementia, characterized by amyloid-beta plaques and neurofibrillary tangles, but its initiating mechanisms remain unclear.
  • MicroRNA-125b (miR-125b) levels are elevated in AD patients, suggesting a potential role in disease pathogenesis.

Purpose of the Study:

  • To investigate the role of microRNA-125b (miR-125b) in the pathological mechanisms of Alzheimer's disease (AD).
  • To determine if miR-125b directly influences tau phosphorylation and associated signaling pathways.

Main Methods:

  • Overexpression and knockdown of miR-125b in primary neurons.
  • Analysis of tau phosphorylation, kinase signaling (p35, cdk5, p44/42-MAPK), and phosphatase/anti-apoptotic factor levels (DUSP6, PPP1CA, Bcl-W).
  • In vivo studies involving hippocampal injection of miR-125b in mice and analysis of AD brains.

Main Results:

  • Overexpression of miR-125b in neurons induced tau hyperphosphorylation and altered kinase/phosphatase signaling.
  • miR-125b directly downregulates phosphatases DUSP6 and PPP1CA, and Bcl-W, which mediate its effects on tau phosphorylation.
  • Suppression of miR-125b reduced tau phosphorylation in neurons.
  • In vivo, miR-125b injection impaired learning and increased tau phosphorylation, with reduced Bcl-W, DUSP6, and PPP1CA levels.
  • DUSP6 and PPP1CA were also found to be reduced in human AD brains.

Conclusions:

  • MicroRNA-125b (miR-125b) plays a significant role in Alzheimer's disease (AD) pathogenesis by promoting pathological tau phosphorylation.
  • The downregulation of phosphatases DUSP6 and PPP1CA by miR-125b is a key mechanism driving tau pathology in AD.
  • Targeting miR-125b may represent a novel therapeutic strategy for Alzheimer's disease.
Keywords:
Alzheimer's diseasekinasesmicroRNA‐125bphosphatasestau phosphorylation

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