An M1/sigma‐1 receptor agonist prevents cognitive deficits, reduces amyloid plaques and neuroinflammation in a transgenic rat model of Alzheimer’s amyloid pathology.
Bibliographic record
Abstract
Abstract Background Acetylcholinesterase inhibitors represent four out of six drugs for treating Alzheimer’s disease (AD), with time‐limited efficacy likely due to the progressive loss of cholinergic neurons. The selective allosteric M1 muscarinic and sigma‐1 receptor agonist Anavex 3‐71 (aka AF710B) [1] takes advantage of the fact that acetylcholine postsynaptic M1 muscarinic brain receptor levels remain unchanged in AD. Previously, Anavex 3‐71 treatment attenuated AD hallmarks in McGill‐R‐Thy1‐APP transgenic rats when administered at advanced stages of the AD‐like pathology [2]. However, preventive strategies instead of late treatment should be more effective in AD. Therefore, we tested whether Anavex 3‐71 administration during early amyloid pathology stages could prevent cognitive impairment, plaque deposition and neuroinflammation. Method Pre‐plaque, seven‐month‐old McGill‐R‐Thy1‐APP rats were subjected to daily oral administration of Anavex 3‐71 (10 µg/kg) for seven months. After one month of drug interruption (wash‐out), we performed Novel Object Recognition (NOR), Morris Water Maze (MWM) and Social Preference (SP) behavioural tests. Subsequently, brains were extracted, fixed and analyzed by histochemistry and immunohistochemistry. Result McGill‐APP rats had deficits in discriminating the novel object in the NOR and locating the hidden platform in the MWM compared to wild‐type littermates. Anavex 3‐71 restored the abilities of McGill‐APP rats in the NOR task to wild‐type levels and partially rescued the deficits in the MWM. In the SP task, Anavex 3‐71‐treated McGill‐APP rats exhibited diminished deficits in SP interaction time with a “stranger rat”. Treatment significantly reduced the number of mature Thioflavin‐S positive plaques in the subiculum compared to vehicle‐treated McGill‐APP rats and diminished the number of diffuse plaques in the cortex and hippocampus. Furthermore, Anavex 3‐71 treatment significantly reduced microglia and astrocyte recruitment towards CA1 hippocampal Aβ‐burdened neurons compared to untreated McGill‐APP rats. Conclusion The long‐lasting effect of Anavex 3‐71 in preventing cognitive decline of McGill‐R‐Thy1‐APP rats, even after a wash‐out period would suggest some preventative, disease‐modifying, properties of the compound over the AD‐like amyloid pathology. This is supported by the attenuation of extracellular Aβ deposition and reduced glial cell recruitment towards hippocampal neurons. [1] Fisher et al., 2016; Neurodegenerative Diseases. https://doi.org/10.1159/000440864 [2] Hall et al., 2018; Alzheimer’s & Dementia. https://doi.org/10.1016/j.jalz.2017.11.009
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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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| 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".