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- W2532252110 abstract "Alois Alzheimer originally described five pathologies within the brains of AD patients: blood vessel abnormalities (cerebrovascular amyloidoisis), intraneuronal fibrils (neurofibrillary tangles), focal deposits (amyloid plaques), glial reactivity (gliosis), and lipoid deposits within non-neuronal cells (lipid accumulations). Lipid metabolism is fundamental for brain development and function, but its roles in normal and pathological neural stem cell (NSC) regulation remain largely unexplored. Moreover, while genetic, biochemical and biomarker studies have made correlative links between abnormal lipid metabolism and AD, further advances have been hindered by technical limitations in the ability to localize, identify, and decipher the biological impacts of dysregulated brain lipids. We used a multidisciplinary approach including mass spectrometry, microarray, in vitro and in vivo stem cell assays, and both mouse and human samples in this study. We localized prominent lipid accumulations to the ependymal cells that form the brain-cerebrospinal fluid (CSF) interface in both AD patients and the 3xTg-AD mouse model. We identified the accumulating lipids as 12 specific triglycerides that are particularly enriched with oleic acid side-chains, and show that infusion of oleic acid into the lateral ventricle of wild-type mice is sufficient to recapitulate the AD-associated triglyceride phenotype. Screening of the plasma and CSF of 3xTg-AD versus control mice showed no differences in circulating levels of AD-associated triglycerides or their component fatty acids, suggesting brain-specific alterations in lipid metabolism. Interestingly, microarray analyses of the subventricular zone proper revealed extensive alterations in lipid-related and neurogenesis/neural stem cell gene expression. In wild-type mice, locally increasing oleic acid was sufficient to recapitulate the AD-associated ependymal triglyceride phenotype and inhibit neural stem cell proliferation. Moreover, inhibiting the rate-limiting enzyme of oleic acid synthesis completely rescued proliferative defects in both the lateral ventricle and hippocampal adult neurogenic niches of 3xTg-AD mice. These studies support a novel pathogenic mechanism in which AD-induced perturbation of fatty acid metabolism within niche ependymal cells suppresses the homeostatic and regenerative functions of adult NSCs." @default.
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- W2532252110 date "2016-07-01" @default.
- W2532252110 modified "2023-10-01" @default.
- W2532252110 title "O1-04-03: Identification of a Novel Lipid-Related Drug Target to Reactivate Adult Neural Stem Cells in Alzheimer's Disease" @default.
- W2532252110 doi "https://doi.org/10.1016/j.jalz.2016.06.312" @default.
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