ELK1 inhibition alleviates amyloid pathology and memory decline by promoting the SYVN1-mediated ubiquitination and degradation of PS1 in Alzheimer’s disease
Why this work is in the frame
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Bibliographic record
Abstract
ELK1 is a member of the E-twenty-six transcription factor family and is usually activated by phosphorylation at Ser383 and Ser389 by extracellular signal-regulated kinase 1/2 (ERK1/2). Dysregulation of ERK1/2 is involved in Alzheimer's disease (AD)-related neuropathogenesis and cognitive impairments. However, the role of ELK1 in AD pathogenesis remains unclear. Here we report that the expression of ELK1 was significantly increased in the brain tissues of patients with AD and AD model mice. The genetic knockdown of ELK1 or inhibition of its phosphorylation by an interfering peptide (TAT-DEF-ELK1 (TDE)) reduced amyloidogenic processing of APP by targeting PS1, consequently inhibiting Aβ generation and alleviating synaptic and memory impairments in APP23/PS45 double-transgenic AD model mice. In addition, we further found that ELK1 regulated the expression of PS1 by competitively inhibiting the interaction between PS1 and its E3 ubiquitin ligase synoviolin (SYVN1), thereby inhibiting the SYVN1-mediated ubiquitination and degradation of PS1. Our results demonstrate that ELK1 aberrantly increases in AD and genetic or pharmacological inhibition of ELK1 can alleviate AD-related pathology and memory impairments by enhancing the SYVN1-mediated PS1 ubiquitination and degradation, indicating that ELK1 may be a novel target for AD treatment.
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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) | 0.000 | 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 it