P4‐218: The liver X receptor agonist GW3965 improves cognitive deficits, reduces beta‐amyloid elevation and suppresses neuronal damage following mild repetitive closed head injury in mice
Bibliographic record
Abstract
Traumatic brain injury (TBI) is a major environmental risk factor for Alzheimer's disease (AD). TBI leads to the formation of neurofibrillary tangles and in, approximately 30% of subjects, amyloid deposits similar to those found in AD. Apolipoprotein E (apoE) is the major lipid carrier in the brain and the best-established genetic risk factor for AD. ApoE genotype also influences recovery after TBI. ApoE receives lipids from ATP-binding cassette transporter A1 (ABCA1) and lipidated apoE facilitates amyloid beta (Aβ) clearance. Agonists of Liver X Receptors (LXR) induce transcription of ABCA1 and apoE, reduce Aβ levels, and improve cognitive function in AD mice. To test the therapeutic utility of LXR agonists for TBI, we determined whether treatment with the LXR agonist GW3965 improves functional, biochemical, and histological outcomes up to 14 days after closed head mild repetitive TBI (mrTBI) in male wild-type (WT) and apoE-/- mice. Mice were subjected to two TBI using a weight drop device. Thirty minutes after the second TBI animals received vehicle or an intraperitoneal bolus of GW3965, followed by feeding with normal or GW3965-containing chow to result in an average dose of 15 mg/kg/day. Mice were assessed with novel object recognition (NOR, cognition), accelerating rotarod (motor function), endogenous Aβ levels, and silver staining (neuronal damage) at 2, 7 and 14d post-TBI. mrTBI impaired NOR memory of WT and apoE-/- mice in both control and treatment groups within 2d with no spontaneous recovery by 14d in untreated mice. GW3965 restored memory in WT but not apoE-/- mice by 7d. Significant motor deficits were observed in injured WT and apoE-/- mice within 24h, followed by spontaneous recovery by 14d independent of treatment. Total soluble Aβ 40 and Aβ 42 levels were significantly elevated in WT and apoE-/- within 2d post-injury, a response that was suppressed by GW3965 in both genotypes. WT mice showed significant neuronal damage at 2d post-mrTBI which was suppressed in treated group. In contrast, apoE-/- mice showed severe axonal damage from 2 to 14d that was unresponsive to GW3965. These results suggest that GW3965 can reduce some of the phenotypes induced by mrTBI in an apoE-dependent manner.
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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 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".