title: Amyloid-beta42 signals tau hyperphosphorylation and compromises neuronal viability by disrupting alkylacylglycerophosphocholine metabolism.
abstract: Perturbation of lipid second messenger networks is associated with the impairment of synaptic function in Alzheimer disease. Underlying molecular mechanisms are unclear. Here, we used an unbiased lipidomic approach to profile alkylacylglycerophosphocholine second messengers in diseased tissue. We found that specific isoforms defined by a palmitic acid (16:0) at the sn-1 position, namely 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16:0 PAF) and 1-O-hexadecyl-sn-glycero-3-phosphocholine (C16:0 lyso-PAF), were elevated in the temporal cortex of Alzheimer disease patients, transgenic mice expressing human familial disease-mutant amyloid precursor protein, and human neurons directly exposed to amyloid-beta(42) oligomers. Acute intraneuronal accumulation of C16:0 PAF but not C16:0 lyso-PAF initiated cyclin-dependent kinase 5-mediated hyperphosphorylation of tau on Alzheimer disease-specific epitopes. Chronic elevation caused a caspase 2 and 3/7-dependent cascade resulting in neuronal death. Pharmacological inhibition of C16:0 PAF signaling, or molecular strategies increasing hydrolysis of C16:0 PAF to C16:0 lyso-PAF, protected human neurons from amyloid-beta(42) toxicity. Together, these data provide mechanistic insight into how disruptions in lipid metabolism can determine neuronal response to accumulating oligomeric amyloid-beta(42).
authors.affiliation: Neural Regeneration Laboratory and Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada, K1H 8M5.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Ryan
authors.forename: Shawn N
authors.initials: SN
authors.lastname: Whitehead
authors.forename: Leigh Anne
authors.initials: LA
authors.lastname: Swayne
authors.forename: Tia C
authors.initials: TC
authors.lastname: Moffat
authors.forename: Weimin
authors.initials: W
authors.lastname: Hou
authors.forename: Martin
authors.initials: M
authors.lastname: Ethier
authors.forename: André J G
authors.initials: AJ
authors.lastname: Bourgeois
authors.forename: Juliet
authors.initials: J
authors.lastname: Rashidian
authors.forename: Alexandre P
authors.initials: AP
authors.lastname: Blanchard
authors.forename: Paul E
authors.initials: PE
authors.lastname: Fraser
authors.forename: David S
authors.initials: DS
authors.lastname: Park
authors.forename: Daniel
authors.initials: D
authors.lastname: Figeys
authors.forename: Steffany A L
authors.initials: SA
authors.lastname: Bennett
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D002154:Calpain / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D000939:Epitopes / Q000276:immunology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D010713:Phosphatidylcholines / Q000378:metabolism*; D010742:Phospholipid Ethers / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020836:Protein Structure, Quaternary; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000939:Epitopes; D010446:Peptide Fragments; D010713:Phosphatidylcholines; D010742:Phospholipid Ethers; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3; C080888:tau-protein kinase; D002154:Calpain; D020169:Caspases