Amyloid‐β protein (Aβ) Glu11 is the major β‐secretase site of β‐site amyloid‐β precursor protein‐cleaving enzyme 1(BACE1), and shifting the cleavage site to Aβ Asp1 contributes to Alzheimer pathogenesis
Why this work is in the frame
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Bibliographic record
Abstract
Cleavage of amyloid-β precursor protein (APP) at the Asp1 β-secretase site of the amyloid-β protein (Aβ) domain by β-site Aβ precursor protein-cleaving enzyme 1 (BACE1) is required for the generation of Aβ, a central component of neuritic plaques in the Alzheimer's disease (AD) brain. In this study, we found that Aβ Glu11 is the major β-secretase site for cleavage of APP by BACE1 to generate soluble secreted APP (sAPPβ)(606) and the C-terminal membrane-bound fragment (CTF)β product C89. Cleavage of C89 by γ-secretase resulted in truncated Aβ generation in a non-amyloidogenic pathway. A familial AD-associated Swedish APP mutation adjacent to Aβ Asp1 shifted the major APP β-secretase cleavage site from Aβ Glu11 to Asp1, resulting in significant increases in sAPPβ596 and CTFβ C99 generation and the C99/89 ratio, in turn leading to increased Aβ production in cultured cells in vitro and transgenic AD model mouse brains in vivo. Furthermore, increased BACE1 expression facilitated APP being processed by the β-secretase processing pathway rather than the α-secretase pathway, leading to more Aβ production. Our results suggest that potentiating BACE1 cleavage of APP at both the Asp1 and Glu11 sites, or shifting the cleavage from the Glu11 site to the Asp1 site, could result in increased Aβ production and facilitate neuritic plaque formation. Our study provides new insights into how alteration of BACE1 expression and β-secretase cleavage site selection could contribute to Alzheimer pathogenesis and the pharmaceutical potential of modulating BACE1 expression and its cleavage site selection.
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 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