Hypothesis & Theory ARTICLE

Front. Physiol., 16 July 2013 | doi: 10.3389/fphys.2013.00168

Using neurolipidomics to identify phospholipid mediators of synaptic (dys)function in Alzheimer's Disease

  • 1Ottawa Institute of Systems Biology, Ottawa, ON, Canada
  • 2Neural Regeneration Laboratory, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada
  • 3CIHR Training Program in Neurodegenerative Lipidomics, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada
  • 4Carleton Immersive Media Studio, Azrieli School of Architecture and Urbanism, Carleton University, Ottawa, ON, Canada

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.

Keywords: neurolipidomics, phospholipid, Alzheimer's Disease, super resolution nanoscopy, lipidomics, mass spectrometry, amyloid-beta, synaptotoxicity

Citation: Bennett SAL, Valenzuela N, Xu H, Franko B, Fai S and Figeys D (2013) Using neurolipidomics to identify phospholipid mediators of synaptic (dys)function in Alzheimer's Disease. Front. Physiol. 4:168. doi: 10.3389/fphys.2013.00168

Received: 10 March 2013; Accepted: 18 June 2013;
Published online: 16 July 2013.

Edited by:

Alessandro Prinetti, University of Milano, Italy

Reviewed by:

Natalia N. Nalivaeva, University of Leeds, UK
Giuseppe Astarita, Georgetown University, USA

Copyright © 2013 Bennett, Valenzuela, Xu, Franko, Fai and Figeys. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

*Correspondence: Steffany A. L. Bennett, Neural Regeneration Laboratory, Department of Biochemistry, Microbiology, and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Rd., Ottawa, ON K1H 8M5, Canada e-mail: sbennet@uottawa.ca

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