title: Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer's Disease.
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.
authors: 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.
authors: Laura K
authors: LK
authors: Hamilton
authors: Department of Chemistry, Faculty of Arts and Sciences, Université de Montréal, Montreal, QC H3C 3J7, Canada.
authors: Martin
authors: M
authors: Dufresne
authors: 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.
authors: Sandra E
authors: SE
authors: Joppé
authors: Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec City, QC G1J 2G3, Canada.
authors: Sarah
authors: S
authors: Petryszyn
authors: 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.
authors: Anne
authors: A
authors: Aumont
authors: Faculty of Pharmacy, Université Laval, Quebec City, QC G1V 0A6, Canada; CHU-Q Research Center, Quebec City, QC G1V 4G2, Canada.
authors: Frédéric
authors: F
authors: Calon
authors: Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
authors: Fanie
authors: F
authors: Barnabé-Heider
authors: Department of Chemistry, Faculty of Arts and Sciences, Université de Montréal, Montreal, QC H3C 3J7, Canada.
authors: Alexandra
authors: A
authors: Furtos
authors: Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec City, QC G1J 2G3, Canada.
authors: Martin
authors: M
authors: Parent
authors: Department of Chemistry, Faculty of Arts and Sciences, Université de Montréal, Montreal, QC H3C 3J7, Canada.
authors: Pierre
authors: P
authors: Chaurand
authors: 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.
authors: Karl J L
authors: KJ
authors: Fernandes
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001344:Autopsy; D049109:Cell Proliferation; D004195:Disease Models, Animal; D050356:Lipid Metabolism; D013058:Mass Spectrometry; D051379:Mice; D046228:Microarray Analysis; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D019301:Oleic Acid / Q000096:biosynthesis; D016548:Prosencephalon / Q000378:metabolism*; D012038:Regeneration; D055153:Stem Cell Niche
chemical_list: D019301:Oleic Acid