Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease

Nat Neurosci. 2008 Nov;11(11):1311-8. doi: 10.1038/nn.2213. Epub 2008 Oct 19.


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 types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alzheimer Disease / complications*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / pharmacology
  • Amyloid beta-Protein Precursor / genetics
  • Analysis of Variance
  • Animals
  • Arachidonic Acids / pharmacology
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Brain / cytology
  • Brain / pathology
  • Case-Control Studies
  • Cell Death / drug effects
  • Cells, Cultured
  • Cognition Disorders / enzymology*
  • Cognition Disorders / etiology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Embryo, Mammalian
  • Enzyme Inhibitors / pharmacology
  • Fatty Acids / metabolism
  • Female
  • Group IV Phospholipases A2 / deficiency*
  • Group IV Phospholipases A2 / metabolism
  • Humans
  • In Vitro Techniques
  • Male
  • Maze Learning / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / drug effects
  • Peptide Fragments / pharmacology
  • Rats
  • Receptors, AMPA / metabolism


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Arachidonic Acids
  • Enzyme Inhibitors
  • Fatty Acids
  • Peptide Fragments
  • Pla2g4a protein, mouse
  • Receptors, AMPA
  • amyloid beta-protein (1-42)
  • arachidonyltrifluoromethane
  • Group IV Phospholipases A2