P2‐045: REGULATION OF RCAN1‐MEDIATED NEURONAL APOPTOSIS APP
Bibliographic record
Abstract
Neuritic plaques, neurofibrillary tangles and neuronal loss are neuropathological hallmarks of Alzheimer's disease (AD). Individuals with Down syndrome (DS), caused by trisomy of chromosome 21, inevitably develop characteristic AD neuropathology after middle age. Amyloid β precursor protein (APP) and regulator of calcineurin 1 (RCAN1) gene on chromosome 21 play a pivotal role in AD pathogenesis. Amyloid β protein (Aβ), the major component of neuritic plaques, is the proteolytic product of APP. APP and RCAN1 are significantly increased in the brains of AD and DS patients, and RCAN1 promotes neuronal apoptosis. However, the mechanism underlying AD pathogenesis and DS is not well defined, and the effect of APP on RCAN1 expression and the role of RCAN1 in APP overexpression-induced neuronal death remain elusive. To study the effect of APP on RCAN1 mediated neuronal apoptosis, we constructed APP and RCAN1 expression plasmids. The plasmids were transiently or stably transfected into cells and neuronal apoptosis and caspase activity were examined by TUNEL staining and Western blot. Gene expression profiling was also performed. We demonstrated that overexpression of APP significantly increased RCAN1 level in cells and transgenic mice, which was independent of its proteolytic products including Aβ. The elevation of RCAN1 was resulted from the reduction of RCAN1 turnover rate. More importantly, we found that overexpression of APP significantly reduced the expression of two proteasome subunits, proteasome α subunit 5 (PSMA5) and proteasome β subunit 7 (PSMB7), which led to proteasomal inhibition and RCAN1 accumulation. Furthermore, APP overexpression facilitated neuronal apoptosis, and APP-induced apoptosis was inhibited by knockdown of RCAN1 expression. The results clearly showed that APP regulates RCAN1-mediated neuronal apoptosis through proteasome pathway. Our study provide new insights into a novel role of APP in AD pathogenesis and the potential of targeting APP-induced proteasomal impairments and RCAN1 accumulation for AD and DS treatment.
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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) | 0.000 | 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) | 0.002 | 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".