Dimethyl fumarate does not mitigate cognitive decline and β-amyloidosis in female APPPS1 mice

Brain Res. 2021 Oct 1;1768:147579. doi: 10.1016/j.brainres.2021.147579. Epub 2021 Jul 4.

Abstract

Introduction: Alzheimer's disease (AD) is the leading cause of dementia and a major global health issue. Currently, only limited treatment options are available to patients. One possibility to expand the treatment repertoire is repurposing of existing drugs such as dimethyl fumarate (DMF). DMF is approved for treatment of multiple sclerosis and previous animal studies have suggested that DMF may also have a beneficial effect for the treatment of AD.

Methods: We used an APPPS1 transgenic model of senile β-amyloidosis and treated female mice orally with DMF in two treatment paradigms (pre and post onset). We quantified learning and memory parameters, β-amyloidosis, and neuroinflammation to determine the potential of DMF as AD therapeutics.

Results: Treatment with DMF had no influence on water maze performance, β-amyloid accumulation, plaque formation, microglia activation, and recruitment of immune cells to the brain. Compared to vehicle-treated animals, oral DMF treatment could not halt or retard disease progression in the mice.

Discussion: Our results do not favour the use of DMF as treatment for AD. While our results stand in contrast to previous findings in other models, they emphasize the importance of animal model selection and suggest further studies to elucidate the mechanisms leading to conflicting results.

Keywords: Alzheimer’s disease; Dimethyl fumarate; Drug repurposing; Mouse model; Multiple sclerosis; Neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / physiopathology
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / metabolism
  • Amyloidosis / drug therapy*
  • Amyloidosis / physiopathology
  • Animals
  • Brain / metabolism
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / physiopathology
  • Dimethyl Fumarate / metabolism
  • Dimethyl Fumarate / pharmacology*
  • Disease Models, Animal
  • Female
  • Hippocampus / metabolism
  • Humans
  • Inflammation / drug therapy
  • Mice
  • Mice, Transgenic
  • Neuroinflammatory Diseases / drug therapy
  • Peptide Fragments / metabolism

Substances

  • APPsalpha protein, mouse
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Peptide Fragments
  • Dimethyl Fumarate