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

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. [Display omitted] •Early NSC impairment in 3xTg-AD mice correlates with SVZ niche lipid accumulations•Similar lipid accumulations are found in the SVZ in postmortem human AD brains•Accumulating SVZ lipids are locally generated, oleic acid-enriched triglycerides•Inhibiting oleic acid signaling or synthesis rescues NSC defects in 3xTg-AD mice Hamilton et al. identify deregulation of niche fatty acid metabolism as a mechanism of disease-induced stem cell impairment. They show that interfering with oleic acid signaling or synthesis rescues NSC proliferation in a mouse model of Alzheimer’s, revealing a potential approach to promote NSC-mediated brain function and repair.