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Updated: Mar 24, 2026

Saccharomyces cerevisiae Models of Alzheimer's Disease to Screen Genes, Mutations, and Chemicals Affecting Amyloid Beta Production by γ-Secretase
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Saccharomyces cerevisiae Models of Alzheimer's Disease to Screen Genes, Mutations, and Chemicals Affecting Amyloid Beta Production by γ-Secretase

Published on: June 24, 2025

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Metformin Facilitates Amyloid-β Generation by β- and γ-Secretases via Autophagy Activation

Sung Min Son1,2, Hong-Joon Shin1, Jayoung Byun1

  • 1Department of Biochemistry & Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.

Journal of Alzheimer'S Disease : JAD
|March 12, 2016
PubMed

Insights

The diabetes drug metformin may worsen Alzheimer's disease (AD) by increasing amyloid-beta (Aβ) generation. Metformin promotes Aβ production in cells and autophagosomes in AD mouse models, potentially exacerbating AD pathogenesis.

Area of Science:

  • Neuroscience
  • Endocrinology
  • Cell Biology

Background:

  • Growing evidence links type 2 diabetes and Alzheimer's disease (AD).
  • Some anti-diabetes drugs are explored for potential AD treatment.
  • Metformin is an insulin-sensitizing anti-diabetes medication.

Purpose of the Study:

  • To investigate the effect of metformin on amyloid-beta (Aβ) generation, a key hallmark of AD.
  • To explore the cellular mechanisms underlying metformin's impact on Aβ production.
  • To assess metformin's effects in an AD mouse model.

Main Methods:

  • Utilized SH-SY5Y cells to study Aβ generation.
  • Administered metformin to Tg6799 AD model mice.
  • Measured amyloid-beta protein precursor (AβPP) cleavage by β- and γ-secretase.
  • Analyzed autophagosome accumulation and γ-secretase activity in autophagic vacuoles.
  • Investigated the role of AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling pathways.

Main Results:

  • Metformin increased Aβ generation in SH-SY5Y cells by promoting AβPP cleavage.
  • Metformin induced autophagosome accumulation in Tg6799 AD model mice.
  • High γ-secretase activity was detected in autophagic vacuoles, suggesting a novel site for Aβ generation.
  • Metformin activated AMPK and suppressed mTOR, leading to autophagy and autophagosome accumulation.

Conclusions:

  • Metformin may exacerbate AD pathogenesis by promoting amyloidogenic AβPP processing.
  • Metformin-induced autophagosome accumulation contributes to increased Aβ generation.
  • The findings challenge the notion that metformin is beneficial for AD treatment and highlight potential risks.
Keywords:
Alzheimer’s diseaseamyloid-β peptidesamyloid-β protein precursorautophagymetformin

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