Open AccessAmyloid-β 42 signals tau hyperphosphorylation and compromises neuronal viability by disrupting alkylacylglycerophosphocholine metabolism
Author(s) -
Scott D. Ryan,
Shawn N. Whitehead,
Leigh Anne Swayne,
Tia C. Moffat,
Weimin Hou,
Martin Ethier,
André J. G. Bourgeois,
Juliet Rashidian,
Alexandre P. Blanchard,
Paul E. Fraser,
David Park,
Daniel Figeys,
Steffany A. L. Bennett
Publication year - 2009
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0905654106
Subject(s) - phosphocholine , hyperphosphorylation , amyloid precursor protein , microbiology and biotechnology , alzheimer's disease , biochemistry , genetically modified mouse , neurodegeneration , chemistry , biology , kinase , transgene , phospholipid , medicine , phosphatidylcholine , disease , membrane , gene
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).