Amyloid-β₄₂ signals tau hyperphosphorylation and compromises neuronal viability by disrupting alkylacylglycerophosphocholine metabolism

Amyloid-β₄₂ 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 fo...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 49; pp. 20936 - 20941
Main Authors: Ryan, Scott D, Whitehead, Shawn N, Swayne, Leigh Anne, Moffat, Tia C, Hou, Weimin, Ethier, Martin, Bourgeois, André J.G, Rashidian, Juliet, Blanchard, Alexandre P, Fraser, Paul E, Park, David S, Figeys, Daniel, Bennett, Steffany A.L
Format: Journal Article
Language:English
Published: National Academy of Sciences 08-12-2009
National Acad Sciences
Subjects:
Alzheimers disease
Biological Sciences
Cell membranes
Hydrolysis
Lipid metabolism
Lipids
Neurons
Oligomers
Phosphorylation
Protein isoforms
Viability
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Summary: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-β₄₂ 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-β₄₂ toxicity. Together, these data provide mechanistic insight into how disruptions in lipid metabolism can determine neuronal response to accumulating oligomeric amyloid-β₄₂.
Bibliography:Edited by Michael V. L. Bennett, Albert Einstein College of Medicine, Bronx, NY, and approved October 14, 2009
Author contributions: S.D.R., L.A.S., T.C.M., W.H., M.E., P.E.F., D.S.P., D.F., and S.A.L.B. designed research; S.D.R., S.N.W., L.A.S., T.C.M., W.H., M.E., A.J.G.B., J.R., A.P.B., and S.A.L.B. performed research; P.E.F. contributed new reagents/analytic tools; S.D.R., L.A.S., T.C.M., W.H., D.S.P., D.F., and S.A.L.B. analyzed data; and S.D.R., D.F., and S.A.L.B. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0905654106