O1‐04‐03: Identification of a Novel Lipid‐Related Drug Target to Reactivate Adult Neural Stem Cells in Alzheimer's Disease
Bibliographic record
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.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".