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Title:   Author  item
                                            SANCHEZ-MEJIA, RENE - UC SAN FRAN, GLADSTONEitem
                                            Newman, Johnitem
                                            TOH, SANDY - UCSF, GLADSTONE INST.item
                                            YU, GUI-QIU - UCSF, GLADSTONE INST.item
                                            ZHOU, YUNGUI - UCSF, GLADSTONE INST.item
                                            SCEARCE-LEVIE, KIMBERLY - UCSF, GLADSTONE INST.item
                                            CHENG, IRENE - UCSF, GLADSTONE INST.item
                                            GAN, LI - UCSF, GLADSTONE INST.item
                                            PALOP, JORGE - UCSF, GLADSTONE INST.item
                                            BONVENTRE, JOSEPH - HARVARD MED.SCHOOLitem
                                            MUCKE, LENNART - UCSF, GLADSTONE INST.
  Submitted to: Nature Neuroscience
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 9/17/2008
                                    Publication  Date: 10/19/2008
                                    Citation: Sanchez-Mejia, R.O., Newman, J.W., Toh, S., Yu, G., Zhou, Y., Scearce-Levie, K., Cheng, I.H., Gan, L., Palop, J.J., Bonventre, J.V., Mucke, L. 2008. PHOSPHOLIPASE A2 REDUCTION AMELIORATES COGNITIVE DEFICITS IN MOUSE MODEL OF ALZHEIMER’S DISEASE. Nature Neuroscience. 11(11): 1311–1318.Interpretive Summary: Transgenic mice expressing the mutant human amyloid precursor protein and the derived amyloid-beta peptides exhibit signs of Alzheimer’s Diesease (AD) including synaptic dysfunction, inflammation, and abnormal cerebrovascular tone. While fatty acid metabolism is known to contribute to these processes, the extent of there involvement in the development and propagation of AD is unknown. Surveying a broad array of lipids in specific regions of the brain in this mouse model of AD suggested increased activity of a specific phospholipase, the group IV isoform of phospholipase A2 (GIVA-PLA2). This enzyme releases lipids like arachidonic acid from phospholipid membranes. The released fatty acid is then transformed by other enzymes into an array of inflammatory mediators. Reducing the activity of this specific enzyme through chemical inhibition reduced neuron-toxicity in cell culture experiments with tissues from the model AD mouse. Moreover, gene ablation protected these mice against developing deficits in learning and memory, behavioral alterations, and premature mortality. Therefore, these results indicate that reducing GIVA-PLA2 activity through either inhibition reduced gene expression may be of benefit in the treatment and prevention of AD.
                                Technical Abstract: Neuronal expression of familial Alzheimer’s disease (AD)-mutant human amyloid precursor proteins (hAPP) and hAPP-derived amyloid-' (A') peptides causes synaptic dysfunction, inflammation, and abnormal cerebrovascular tone in transgenic mice. Fatty acids are involved in these processes, but their contribution to AD pathogenesis is uncertain. A lipidomics approach to broadly profile fatty acids in brain tissues of hAPP mice revealed an increase in arachidonic acid and its metabolites, suggesting increased activity of the group IV isoform of phospholipase A2 (GIVA-PLA2). Increased levels of activated GIVA-PLA2 correlated with A' levels in hAPP mice in brain regions vulnerable to AD. A' caused a dose-dependent increase in GIVA-PLA2 phosphorylation in neuronal cultures. Inhibition of GIVA-PLA2 diminished A'-mediated 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 of benefit in the treatment and prevention of AD.


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