Phospholipase A2reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease Academic Article uri icon


MeSH Major

  • Alzheimer Disease
  • Cognition Disorders
  • Group IV Phospholipases A2


  • Neuronal expression of familial Alzheimer's disease-mutant human amyloid precursor protein (hAPP) and hAPP-derived amyloid-beta (Abeta) peptides causes synaptic dysfunction, inflammation and abnormal cerebrovascular tone in transgenic mice. Fatty acids may be involved in these processes, but their contribution to Alzheimer's disease pathogenesis is uncertain. We used a lipidomics approach to generate a broad profile of fatty acids in brain tissues of hAPP-expressing mice and found an increase in arachidonic acid and its metabolites, suggesting increased activity of the group IV isoform of phospholipase A(2) (GIVA-PLA(2)). The levels of activated GIVA-PLA(2) in the hippocampus were increased in individuals with Alzheimer's disease and in hAPP mice. Abeta caused a dose-dependent increase in GIVA-PLA(2) phosphorylation in neuronal cultures. Inhibition of GIVA-PLA(2) diminished Abeta-induced neurotoxicity. Genetic ablation or reduction of GIVA-PLA(2) protected hAPP mice against Abeta-dependent deficits in learning and memory, behavioral alterations and premature mortality. Inhibition of GIVA-PLA(2) may be beneficial in the treatment and prevention of Alzheimer's disease.

publication date

  • November 2008



  • Academic Article



  • eng

PubMed Central ID

  • PMC2597064

Digital Object Identifier (DOI)

  • 10.1038/nn.2213

PubMed ID

  • 18931664

Additional Document Info

start page

  • 1311

end page

  • 8


  • 11


  • 11