BACE2, as a novel APP θ‐secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
Amyloid beta protein (Abeta), the major component of neuritic plaques in Alzheimer's disease (AD), is derived from APP by sequential cleavages of beta- and gamma-secretases. Beta-site APP cleaving enzyme 1 (BACE1) is the major beta-secretase in vivo. Beta-site APP cleaving enzyme 2 (BACE2) is the homologue of BACE1. The majority of people with Down syndrome (DS), also called Trisomy 21 syndrome, will develop AD neuropathology after middle age. We and others have shown that APP C99, the major beta-secretase product, and Abeta are markedly increased in DS. Since BACE2 is located on chromosome 21, it is speculated that BACE2 may play a role in AD pathogenesis in DS. In this report we found that BACE2 cleaves APP at a novel theta site downstream of the alpha site, abolishing Abeta production. Overexpression of BACE2 by lentivirus markedly reduced Abeta production in primary neurons derived from Swedish mutant APP transgenic mice. Despite an extra copy of the BACE2 gene in DS and the increase of its transcription, BACE2 protein levels are unchanged. Our data clearly demonstrate that BACE2, as a novel theta-secretase to cleave APP within the Abeta domain, is not involved in the AD pathogenesis of DS patients; instead, therapeutic interventions that potentiate BACE2 may prevent AD pathogenesis.
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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 | 0.001 | 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