Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice

Brain Behav Immun. 2018 Mar;69:351-363. doi: 10.1016/j.bbi.2017.12.009. Epub 2017 Dec 15.

Abstract

Alzheimer'sdisease(AD) is characterized by deposition of amyloid-β (Aβ)plaques, neurofibrillary tangles, andneuronal loss, accompaniedbyneuroinflammation. Neuroinflammatoryprocesses are thought to contribute toAD pathophysiology. Metformin has been reported to have anti-inflammatory efficacy. However, whether metformin is responsible for the anti-neuroinflammationand neuroprotection on APPswe/PS1ΔE9 (APP/PS1) mice remains unclear. Here we showed that metformin attenuated spatial memory deficit, neuron loss in the hippocampus and enhanced neurogenesis in APP/PS1 mice. In addition, metformin administration decreased amyloid-β (Aβ)plaque load and chronic inflammation (activated microglia and astrocytes as well as pro-inflammatory mediators) in the hippocampus and cortex. Further study demonstrated that treatment with metformin enhanced cerebral AMPK activation. Meanwhile, metformin notably suppressed the activation of P65 NF-κB, mTOR and S6K, reduced Bace1 protein expression. Our data suggest that metformin can exert functional recovery of memory deficits and neuroprotective effect on APP/PS1 mice via triggering neurogenesis and anti-inflammation mediated by regulating AMPK/mTOR/S6K/Bace1 and AMPK/P65 NF-κB signaling pathways in the hippocampus, which may contribute to improvement in neurological deficits.

Keywords: AMPK; Alzheimer disease; Metformin; NF-κB; Neurogenesis; Neuroinflammation; mTOR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Male
  • Memory Disorders / metabolism
  • Memory Disorders / pathology
  • Memory Disorders / prevention & control*
  • Metformin / pharmacology
  • Metformin / therapeutic use*
  • Mice
  • Mice, Transgenic
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • Plaque, Amyloid / prevention & control*
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Neuroprotective Agents
  • Presenilin-1
  • Metformin