Mechanisms of Memory Deficits in Mouse Models of Alzheimer's Disease
Bibliographic record
Abstract
Alzheimer’s disease (AD), a neurodegenerative disorder initially characterized by mild memory impairments, progresses to global cognitive deficits and eventually death. AD pathological hallmarks are plaques and tangles. Acute and chronic effects of familial Alzheimer’s disease (FAD) genes were examined in WT and transgenic mice respectively. We used viral vectors to acutely express FAD genes encoding the Swedish, Indiana, and Swedish and Indiana double mutation, of amyloid precursor protein (APP) in the hippocampal CA1 region (which exhibits early AD pathology) in mice. Acute expression of FAD genes produced deficits in the formation but not retreival of spatial memory. We next examined spine density as changes are thought to affect synaptic plasticity. Acute expression of FAD genes did not affect the structure (dendritic length, intersections and nodes), but decreased spine density in infected CA1 neurons. Amyloid beta (Aβ) binds to excitatory synapses, particularly to GluA2-AMPA receptors (AMPAR) leading to endocytosis. Therefore,, acute CA1 expression of FAD genes produced spatial memory formation deficits mediated by impairments in dendritic spine plasticity and transmission via AMPAR endocytosis. Additionally, infusing GluA2-3Y, a peptide that prevents Aβ induced AMPAR endocytosis in acute and chronic (TgCRND8) AD mouse models expressing double mutated APP genes, was similarly able to rescue the spatial memory and spine density deficits. Since the transcription factor CREB is critical for normal memory formation across species, we investigated its role in TgCRND8 mice. We observed additional deficits in the dorsal hippocampus of TgCRND8 mice, including 1) biochemistry (CREB activation), 2) neuronal structure, and 3) neuronal network activity. Moreover, locally and acutely increasing CREB function in the CA1 region of TgCRND8 mice was sufficient to restore function in each domain independent of plaque load or aggregated Aβ levels. Together, these studies indicate that targeting GluA2 or CREB may be useful therapeutic strategies in treating AD.
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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) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".