P4‐163: A model for sterol dysregulation in Alzheimer's disease brain
Bibliographic record
Abstract
Altered CH metabolism and up-regulation of heme oxygenase-1 (HO-1) are characteristic of AD-affected neural tissues. We recently determined that HO-1 over-expression suppresses total CH levels by augmenting liver X receptor-mediated CH efflux and enhances oxysterol formation in cultured astroglia. Lipids and proteins were extracted from post-mortem human frontal cortex and cerebellum (control) derived from subjects with sporadic AD, mild cognitive impairment (MCI) and no cognitive impairment (NCI; n=17 per group) enrolled in the Religious Orders Study, an ongoing clinical-pathologic study of aging and AD. Total CH, CH precursors and relevant oxysterols were quantified by GC-MS. HO-1 protein concentrations were measured by ELISA. The relationships of sterol/oxysterol levels to HO-1 concentrations and clinical/demographic variables were determined by multivariate analysis. Decreased CH and increased oxysterol concentrations in the cortex correlated significantly with HO-1 levels in MCI and AD, but not NCI. In cortex but not cerebellum, specific oxysterols correlated with disease state, increasing neuropathological burden, neuropsychological decline, age, E4 genotype and gender. In conjunction with our previous in vitro data, we suggest a model for altered sterol homeostasis in MCI and AD: In the normal aging brain, sterol homeostasis is maintained by pathways governing baseline CH biosynthesis, CH efflux and oxysterol formation. In NCI, glial HO-1 expression and its influence on sterol metabolic pathways are minimal. In initial, ‘compensated' MCI and AD, enhanced HO-1 expression stimulates CH biosynthesis, oxysterol formation and CH efflux by the astroglial compartment. Glial CH efflux (facilitating CH delivery for neuronal repair and egress across the blood-brain barrier) exceeds biosynthesis, and CH levels in affected brain are normal or diminished. In ‘de-compensated' AD, massive uptake of CH (derived from widespread neuronal degeneration) overwhelms glial efflux pathways resulting in increased brain CH levels. The latter suppresses de novo CH biosynthesis (negative servomechanism as in peripheral tissues) and brain CH precursor levels decline. A rationale whereby prevention or amelioration of the ‘decompensated' stage of brain CH homeostasis may prove neuroprotective in AD will be discussed.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".