O1‐04‐03: Identification of a Novel Lipid‐Related Drug Target to Reactivate Adult Neural Stem Cells in Alzheimer's Disease

• DOI: 10.1016/j.jalz.2016.06.312
• Publication Date: 2016-10-17T07:22:00Z
• Authors: Laura K. Hamilton; Sandra E. Joppe; Martin Dufresne; Pierre Chaurand; Sarah Petryszyn; Martin Parent; Karl J.L. Fernandes; Anne Aumont; Alexandra Furtos; Frederic Calon
• Keywords: 03 medical and health sciences; 0302 clinical medicine

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 non-neuronal cells (lipid accumulations). Lipid metabolism is fundamental for brain development function, but its roles in normal pathological neural stem cell (NSC) regulation remain largely unexplored. Moreover, while genetic, biochemical biomarker studies have made correlative links between abnormal lipid AD, further advances been hindered by technical limitations ability to localize, identify, decipher biological impacts dysregulated lipids. We used a multidisciplinary approach including mass spectrometry, microarray, vitro vivo assays, both mouse human samples this study. localized prominent accumulations ependymal that form brain-cerebrospinal fluid (CSF) interface patients 3xTg-AD model. identified accumulating lipids as 12 specific triglycerides are particularly enriched with oleic acid side-chains, show infusion into lateral ventricle wild-type mice sufficient recapitulate AD-associated triglyceride phenotype. Screening plasma CSF versus control showed no differences circulating levels or their component fatty acids, suggesting brain-specific alterations metabolism. Interestingly, microarray analyses subventricular zone proper revealed extensive lipid-related neurogenesis/neural gene expression. In mice, locally increasing was phenotype inhibit proliferation. inhibiting rate-limiting enzyme synthesis completely rescued proliferative defects hippocampal adult neurogenic niches mice. These support novel pathogenic mechanism which AD-induced perturbation niche suppresses homeostatic regenerative functions NSCs.