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Scientific article
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A Signaling Lipid Associated with Alzheimer's Disease Promotes Mitochondrial Dysfunction

Published inScientific Reports, vol. 6, 19332
Publication date2016
Abstract

Fundamental changes in the composition and distribution of lipids within the brain are believed to contribute to the cognitive decline associated with Alzheimer's disease (AD). The mechanisms by which these changes in lipid composition affect cellular function and ultimately cognition are not well understood. Although "candidate gene" approaches can provide insight into the effects of dysregulated lipid metabolism they require a preexisting understanding of the molecular targets of individual lipid species. In this report we combine unbiased gene expression profiling with a genome-wide chemogenomic screen to identify the mitochondria as an important downstream target of PC(O-16:0/2:0), a neurotoxic lipid species elevated in AD. Further examination revealed that PC(O-16:0/2:0) similarly promotes a global increase in ceramide accumulation in human neurons which was associated with mitochondrial-derived reactive oxygen species (ROS) and toxicity. These findings suggest that PC(O-16:0/2:0)-dependent mitochondrial dysfunction may be an underlying contributing factor to the ROS production associated with AD.

Keywords
  • Alzheimer Disease/genetics/metabolism/pathology
  • Amyloid beta-Peptides/metabolism
  • Cell Line
  • Cells
  • Cultured
  • Ceramides/metabolism
  • Gene Expression Profiling
  • Humans
  • Lipid Metabolism/genetics
  • Mechanistic Target of Rapamycin Complex 2
  • Membrane Potential
  • Mitochondrial
  • Mitochondria/genetics/metabolism
  • Multiprotein Complexes/metabolism
  • Neurons/metabolism
  • Open Reading Frames
  • Oxidative Stress
  • Reactive Oxygen Species/metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases/metabolism
Research group
Citation (ISO format)
KENNEDY, Michael A et al. A Signaling Lipid Associated with Alzheimer’s Disease Promotes Mitochondrial Dysfunction. In: Scientific Reports, 2016, vol. 6, p. 19332. doi: 10.1038/srep19332
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Article (Published version)
accessLevelPublic
Identifiers
ISSN of the journal2045-2322
411views
159downloads

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