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Cell Stem Cell. 2015 Oct 1;17(4):397-411. doi: 10.1016/j.stem.2015.08.001. Epub 2015 Aug 27.

Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer's Disease.

Author information

1
Research Center of the University of Montreal Hospital (CRCHUM), Montreal, QC H2X 0A9, Canada; CNS Research Group (GRSNC), Montreal, QC H3T 1J4, Canada; Department of Neurosciences, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada.
2
Department of Chemistry, Faculty of Arts and Sciences, Université de Montréal, Montreal, QC H3C 3J7, Canada.
3
Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec City, QC G1J 2G3, Canada.
4
Faculty of Pharmacy, Université Laval, Quebec City, QC G1V 0A6, Canada; CHU-Q Research Center, Quebec City, QC G1V 4G2, Canada.
5
Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
6
Research Center of the University of Montreal Hospital (CRCHUM), Montreal, QC H2X 0A9, Canada; CNS Research Group (GRSNC), Montreal, QC H3T 1J4, Canada; Department of Neurosciences, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada. Electronic address: karl.jl.fernandes@umontreal.ca.

Abstract

Lipid metabolism is fundamental for brain development and function, but its roles in normal and pathological neural stem cell (NSC) regulation remain largely unexplored. Here, we uncover a fatty acid-mediated mechanism suppressing endogenous NSC activity in Alzheimer's disease (AD). We found that postmortem AD brains and triple-transgenic Alzheimer's disease (3xTg-AD) mice accumulate neutral lipids within ependymal cells, the main support cell of the forebrain NSC niche. Mass spectrometry and microarray analyses identified these lipids as oleic acid-enriched triglycerides that originate from niche-derived rather than peripheral lipid metabolism defects. In wild-type mice, locally increasing oleic acid was sufficient to recapitulate the AD-associated ependymal triglyceride phenotype and inhibit NSC proliferation. Moreover, inhibiting the rate-limiting enzyme of oleic acid synthesis rescued proliferative defects in both adult neurogenic niches of 3xTg-AD mice. These studies support a pathogenic mechanism whereby AD-induced perturbation of niche fatty acid metabolism suppresses the homeostatic and regenerative functions of NSCs.

PMID:
26321199
DOI:
10.1016/j.stem.2015.08.001
[Indexed for MEDLINE]
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