Amyloid Beta Accumulation in Mouse Brain in Response to Vitamin D Receptor Ligands, Cholesterol and Age
Bibliographic record
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the accumulation of amyloid beta (Aβ) plaques. Aging, vitamin D deficiency and high cholesterol are AD risk factors. Activation of the vitamin D receptor (VDR) increases P-gp expression for Aβ efflux and lowers peripheral cholesterol. However, the effect on neprilysin for Aβ degradation and β-secretase protein (BACE-1) for Aβ synthesis is not entirely defined. We described in vitro strategies for identifying selective VDR analogs for activation of brain P-gp but not intestinal calcium channel, TRPV6. Upon improving the GAL4-hVDR luciferase reporter assay by adding ketoconazole to inhibit the bioactivation and degradation enzymes, we showed that the Teijin analogs induce brain P-gp but remain hypercalcemic. We then demonstrated, with various hypercholesterolemic mouse models: C57BL/6 mice fed high fat/high cholesterol (WD) or vitamin D deficient diets or Ldlr-/- mice; that plasma and liver cholesterol but not brain cholesterol levels were elevated with WD and decreased with 1,25(OH)2D3 or dietary vitamin D3. 1,25(OH)2D3 and atorvastatin co-administered to C57BL/6 mice lowered brain Aβ40 significantly, without affecting brain cholesterol. 1,25(OH)2D3 treatment increased P-gp expression in the young (8-weeks) and middle-aged (4-8 months) but not old (10-months) C57BL/6 mice and decreased the Aβ42/Aβ40 ratio for the middle-aged and old mice. Significant, negative correlations were observed for P-gp protein and mRNA expressions of neprilysin and Cyp46a1, the brain cholesterol metabolic enzyme whereas a significant, positive correlation was observed for Bace-1 protein vs. brain Aβ levels. Overall, brain cholesterol did not change nor correlate with brain Aβ although plasma cholesterol and brain Aβ levels were positively correlated. It is concluded that high peripheral cholesterol and age-related changes in P-gp, neprilysin, and Cyp46a1 are risk factors for brain Aβ accumulation. Effects in brain cholesterol may be revealed in future experiments with longer duration of WD and 1,25(OH)2D3 and atorvastatin treatment.
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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 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.002 |
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".