Article abstract
Nature Neuroscience 11, 1311 - 1318 (2008)
Published online: 19 October 2008 | doi:10.1038/nn.2213
Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease
Rene O Sanchez-Mejia1,2,7, John W Newman3, Sandy Toh1,4, Gui-Qiu Yu1, Yungui Zhou1, Brian Halabisky1, Moustapha Cissé1, Kimberly Scearce-Levie1, Irene H Cheng1, Li Gan1, Jorge J Palop1, Joseph V Bonventre5 & Lennart Mucke1,4,6
Abstract
Neuronal expression of familial Alzheimer's disease–mutant human amyloid precursor protein (hAPP) and hAPP-derived amyloid-
(A) 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. A caused a dose-dependent increase in GIVA-PLA2 phosphorylation in neuronal cultures. Inhibition of GIVA-PLA2 diminished A-induced neurotoxicity. Genetic ablation or reduction of GIVA-PLA2 protected hAPP mice against A-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.
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, California 94158, USA.
- Department of Neurosurgery, University of California San Francisco, Box 0112, San Francisco, California 94143, USA.
- Department of Nutrition, University of California Davis, and Western Human Nutrition Research Center, US Department of Agriculture, 12830 Academic Surge, Davis, California 95616, USA.
- Neuroscience Graduate Training Program, University of California San Francisco, Box 1230, San Francisco, California 94143, USA.
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
- Department of Neurology, Box 1230, University of California San Francisco, San Francisco, California 94143, USA.
- Present address: Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, GRB-241, Boston, Massachusetts 02114, USA.
Correspondence to: Lennart Mucke1,4,6 e-mail: lmucke@gladstone.ucsf.edu
Correspondence to: Rene O Sanchez-Mejia1,2,7 e-mail: rene_sanchez@post.harvard.edu
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