P1–085: The effect of APP mutations on BACE1 cleavage and APP processing
Bibliographic record
Abstract
Neuritic plaque, formed by the deposition of amyloid β protein (Aβ), is one of hallmarks of Alzheimer's disease (AD). Aβ is produced from sequential cleavage of the amyloid β precursor protein (APP) by β- and γ-secretases. Beta-site APP cleaving enzyme 1 (BACE1) is the β-secretase essential for Aβ generation. Dysregulation of BACE1 has been shown to play an important in AD pathogenesis and inhibition of BACE1-mediated Aβ generation may have therapeutic implications for AD treatment. Mutations in APP cause early onset of familial Alzheimer's Disease and most APP mutations are autosomal dominant mutations. Many of these pathogenic mutations resulted in abnormal APP processing. To study the effect of mutations in APP gene on BACE1 cleavage and APP processing, we constructed APP expression plasmids carrying mutations around Aβ N-terminus including Swedish, Italian and Icelandic. The mutant APP expression plasmids were transiently or stably transfected into HEK293 and SH-SY5Y cells as well as BACE1 stable cells. APP processing, Aβ production, and BACE1 cleavage pattern were examined by Western blot and ELISA assays. We found that BACE1 predominantly cleaved APP at the Glu11 site of Aβ domain to generate C89, and APP mutations differentially affected BACE1 cleavage site selection and altered C99/C89 ratio. These APP CTFβ pattern changes resulted in abnormal Aβ production. Our work provides new insights into how these APP mutations contribute to AD pathogenesis by altering BACE1 cleavages.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.000 | 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 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".