Pharmacological inhibition of PLK2 kinase activity mitigates cognitive decline but aggravates APP pathology in a sex-dependent manner in APP/PS1 mouse model of Alzheimer's disease
Bibliographic record
Abstract
Converging evidence from clinical and experimental studies suggest the potential significance of Polo-like kinase 2 (PLK2) in regulating the phosphorylation and toxicity of the Alzheimer's disease (AD)-related protein, amyloid precursor protein (APP). These findings have prompted various experimental trials aimed at inhibiting PLK2 kinase activity in different transgenic mouse models of AD. While positive impacts on cognitive decline were reported in these studies, the cellular effects remained controversial. In the present study, we sought to assess the cognitive and cellular consequences of chronic PLK2 inhibitor treatment in the APP/PS1 transgenic mouse model of AD. First, we confirmed that inhibiting PLK2 prevented cognitive decline in a sex-dependent manner, particularly by enhancing working memory in male APP/PS1 mice. Surprisingly, cellular analysis revealed that treatment with PLK2 inhibitor increased the load of amyloid plaques and elevated levels of soluble amyloid β (Aβ) 40 and Aβ42 in the cortex, as well as insoluble Aβ42 in the hippocampus of female mice, without affecting APP pathology in males. These results underscore the potential of PLK2 inhibition to mitigate cognitive symptoms in males. However, paradoxically, it intensifies amyloid pathology in females by enhancing APP amyloidogenic processing, creating a controversial aspect to its therapeutic impact. Overall, these data highlight the sex-dependent nature of the effects of PLK2 inhibition, which may also be influenced by the genetic background of the transgenic mouse model utilized.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".