Neuronal expression of familial Alzheimer's disease–mutant human amyloid precursor protein (hAPP) and hAPP-derived amyloid-β (Aβ) 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 A2 (GIVA-PLA2). The levels of activated GIVA-PLA2 in the hippocampus were increased in individuals with Alzheimer's disease and in hAPP mice. Aβ caused a dose-dependent increase in GIVA-PLA2 phosphorylation in neuronal cultures. Inhibition of GIVA-PLA2 diminished Aβ-induced neurotoxicity. Genetic ablation or reduction of GIVA-PLA2 protected hAPP mice against Aβ-dependent deficits in learning and memory, behavioral alterations and premature mortality. Inhibition of GIVA-PLA2 may be beneficial in the treatment and prevention of Alzheimer's disease.
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We thank the Alzheimer's Disease Research Center at University of California San Francisco for postmortem brain tissues; T. Wu, A. Thwin and H. Solanoy for technical support; C. McCulloch for help with statistical analysis; G. Howard and S. Ordway for editorial review; J. Carroll and C. Goodfellow for preparation of graphics; and D. McPherson for administrative assistance. The study was supported by US National Institutes of Health (NIH) grants AG011385, AG022074 and NS041787 to L.M., AG028233 to R.O.S.-M. and US NIH/National Center for Research Resources grant CO6RR018928 to the J. David Gladstone Institutes. Additional support was provided by the US Department of Agriculture Agricultural Research Service 5306-51530-016-00D to J.W.N. and from the NIH National Institute of Diabetes and Digestive and Kidney Diseases DK 054741 to J.V.B.
Lennart Mucke has a consulting agreement with Merck.
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Sanchez-Mejia, R., Newman, J., Toh, S. et al. Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease. Nat Neurosci 11, 1311–1318 (2008). https://doi.org/10.1038/nn.2213
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