Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer's Disease
Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer's Disease
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DOI：
10.1016/j.stem.2015.08.001
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发表时间：
2015-10-01
期刊：
影响因子：
23.9
通讯作者：
Fernandes, Karl J. L.
中科院分区：
文献类型：
--
作者：
Hamilton, Laura K.;Dufresne, Martin;Fernandes, Karl J. L.
脂质代谢是大脑发育和功能的基础，但其在正常和病理性神经干细胞（NSC）调节中的作用在很大程度上尚未探索。在这里，我们发现了一个脂肪酸介导的机制，抑制内源性神经干细胞的活动在阿尔茨海默病（AD）。我们发现，死后AD脑和三转基因阿尔茨海默病（3xTg-AD）小鼠室管膜细胞，前脑NSC龛的主要支持细胞内积累中性脂质。质谱和微阵列分析确定这些脂质为富含油酸的甘油三酯，其来源于生态位衍生的而不是外周脂质代谢缺陷。在野生型小鼠中，局部增加油酸足以重现AD相关室管膜甘油三酯表型并抑制NSC增殖。此外，抑制油酸合成的限速酶拯救了3xTg-AD小鼠的两个成年神经原性小生境中的增殖缺陷。这些研究支持了AD诱导的小生境脂肪酸代谢紊乱抑制神经干细胞的稳态和再生功能的致病机制。
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.