Amyloid-beta42 signals tau hyperphosphorylation and compromises neuronal viability by disrupting alkylacylglycerophosphocholine metabolism.
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).
Ryan
Scott D
SD
Neural Regeneration Laboratory and Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada, K1H 8M5.
Whitehead
Shawn N
SN
Swayne
Leigh Anne
LA
Moffat
Tia C
TC
Hou
Weimin
W
Ethier
Martin
M
Bourgeois
André J G
AJ
Rashidian
Juliet
J
Blanchard
Alexandre P
AP
Fraser
Paul E
PE
Park
David S
DS
Figeys
Daniel
D
Bennett
Steffany A L
SA
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*
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