Increased BACE1 maturation contributes to the pathogenesis of Alzheimer's disease in Down syndrome
Bibliographic record
Abstract
Almost all Down syndrome (DS) patients develop characteristic Alzheimer's disease (AD) neuropathology, including neuritic plaques and neurofibrillary tangles, after middle age. The mechanism underlying AD neuropathology in DS has been unknown. Abeta is the central component of neuritic plaques and is generated from APP by cleavage by the beta- and gamma-secretases. Here we show that beta-secretase activity is markedly elevated in DS. The ratio of mature to immature forms of BACE1 is altered in DS. DS has significantly higher levels of mature BACE1 proteins in Golgi than normal controls. Time-lapse live image analysis showed that BACE1 proteins were predominantly immobile in Golgi in DS cells, while they underwent normal trafficking in controls. Thus, overproduction of Abeta in DS is caused by abnormal BACE1 protein trafficking and maturation. Our results provide a novel molecular mechanism by which AD develops in DS and support the therapeutic potential of inhibiting BACE1 in AD and DS.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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) | 0.001 | 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 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".