title: Phospholipase d2 ablation ameliorates Alzheimer's disease-linked synaptic dysfunction and cognitive deficits.
abstract: Growing evidence implicates aberrant lipid signaling in Alzheimer's disease (AD). While phospholipases A2 and C have been recently shown to mediate key actions of amyloid β-peptide (Aβ) through a dysregulation of arachidonic acid and phosphatidylinositol-4,5-bisphosphate metabolism, respectively, the role of phospholipase D (PLD) has so far remained elusive. PLD produces phosphatidic acid (PA), a bioactive lipid involved in multiple aspects of cell physiology, including signaling and membrane trafficking processes. Here we show that oligomeric Aβ enhances PLD activity in cultured neurons and that this stimulatory effect does not occur upon ablation of PLD2 via gene targeting. Aβ fails to suppress long-term potentiation in PLD2-deficient hippocampal slices, suggesting that PLD2 is required for the synaptotoxic action of this peptide. In vivo PLD activity, as assessed by detection of phosphatidylethanol levels using mass spectrometry (MS) following ethanol injection, is also increased in the brain of a transgenic mouse model of AD (SwAPP). Furthermore, Pld2 ablation rescues memory deficits and confers synaptic protection in SwAPP mice despite a significant Aβ load. MS-based lipid analysis of Pld2 mutant brains in the presence or absence of the SwAPP transgene unmasks striking crosstalks between different PA species. This lipid analysis shows an exquisite acyl chain specificity and plasticity in the perturbation of PA metabolism. Collectively, our results point to specific molecular species of PA as key modulators of AD pathogenesis and identify PLD2 as a novel potential target for therapeutics.
authors.affiliation: Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Tiago Gil
authors.initials: TG
authors.lastname: Oliveira
authors.forename: Robin B
authors.initials: RB
authors.lastname: Chan
authors.forename: Huasong
authors.initials: H
authors.lastname: Tian
authors.forename: Mikael
authors.initials: M
authors.lastname: Laredo
authors.forename: Guanghou
authors.initials: G
authors.lastname: Shui
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Staniszewski
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Tae-Wan
authors.initials: TW
authors.lastname: Kim
authors.forename: Karen E
authors.initials: KE
authors.lastname: Duff
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.forename: Gilbert
authors.initials: G
authors.lastname: Di Paolo
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal; D002461:Cell Line, Transformed; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D003213:Conditioning, Psychological / Q000502:physiology; D004195:Disease Models, Animal; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004963:Estrenes / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005239:Fear / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D013058:Mass Spectrometry / Q000379:methods; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016716:PC12 Cells / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D010739:Phospholipase D / Q000172:deficiency* / Q000235:genetics; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D013569:Synapses / Q000235:genetics*; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D004963:Estrenes; D010446:Peptide Fragments; D011760:Pyrrolidinones; C075222:amyloid beta-protein (1-42); C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D049452:Green Fluorescent Proteins; C105606:phospholipase D2; D010739:Phospholipase D; C106801:phospholipase D1