title: Using neurolipidomics to identify phospholipid mediators of synaptic (dys)function in Alzheimer's Disease.
abstract: Not all of the mysteries of life lie in our genetic code. Some can be found buried in our membranes. These shells of fat, sculpted in the central nervous system into the cellular (and subcellular) boundaries of neurons and glia, are themselves complex systems of information. The diversity of neural phospholipids, coupled with their chameleon-like capacity to transmute into bioactive molecules, provides a vast repertoire of immediate response second messengers. The effects of compositional changes on synaptic function have only begun to be appreciated. Here, we mined 29 neurolipidomic datasets for changes in neuronal membrane phospholipid metabolism in Alzheimer's Disease (AD). Three overarching metabolic disturbances were detected. We found that an increase in the hydrolysis of platelet activating factor precursors and ethanolamine-containing plasmalogens, coupled with a failure to regenerate relatively rare alkyl-acyl and alkenyl-acyl structural phospholipids, correlated with disease severity. Accumulation of specific bioactive metabolites [i.e., PC(O-16:0/2:0) and PE(P-16:0/0:0)] was associated with aggravating tau pathology, enhancing vesicular release, and signaling neuronal loss. Finally, depletion of PI(16:0/20:4), PI(16:0/22:6), and PI(18:0/22:6) was implicated in accelerating Aβ42 biogenesis. Our analysis further suggested that converging disruptions in platelet activating factor, plasmalogen, phosphoinositol, phosphoethanolamine (PE), and docosahexaenoic acid metabolism may contribute mechanistically to catastrophic vesicular depletion, impaired receptor trafficking, and morphological dendritic deformation. Together, this analysis supports an emerging hypothesis that aberrant phospholipid metabolism may be one of multiple critical determinants required for Alzheimer disease conversion.
authors.affiliation: Ottawa Institute of Systems Biology Ottawa, ON, Canada ; Neural Regeneration Laboratory, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa Ottawa, ON, Canada ; CIHR Training Program in Neurodegenerative Lipidomics, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa Ottawa, ON, Canada.
authors.forename: Steffany A L
authors.initials: SA
authors.lastname: Bennett
authors.forename: Nicolas
authors.initials: N
authors.lastname: Valenzuela
authors.forename: Hongbin
authors.initials: H
authors.lastname: Xu
authors.forename: Bettina
authors.initials: B
authors.lastname: Franko
authors.forename: Stephen
authors.initials: S
authors.lastname: Fai
authors.forename: Daniel
authors.initials: D
authors.lastname: Figeys
keywords: Alzheimer's Disease; amyloid-beta; lipidomics; mass spectrometry; neurolipidomics; phospholipid; super resolution nanoscopy; synaptotoxicity