P4‐011: AP‐3 but not AP‐1 mediates the direct and rapid trafficking of APP from Golgi to lysosomes
Bibliographic record
Abstract
The Amyloid Hypothesis posits that neuronal dysfunction and loss in AD results from the production of an increased relative amount of β -amyloid 42 (A β). Aβ is produced from sequential cleavage of amyloid precursor protein by β -secretase and γ -secretase enzymes. Slightly variable cleavage by the γ -secretase results in Aβ products ranging from 38-43 residues. Therefore, it is important to understand the factors influencing γ -secretase activity to limit the production of toxic Aβ 42. It has previously been shown that γ -secretase has differential cleavage in different subcellular milieu. However, the subcellular organelle responsible for γ -secretase cleavage remains contentious, with evidence for APP cleavage in many compartments including the ER, Golgi, plasma membrane, autophagosomes or endosomes/lysosomes. Our lab has shown that APP and γ -secretase is enriched in lysosomal fractions. While the subcellular trafficking of APP most likely plays an important role in determining the location of APP cleavage by γ -secretase, no studies have followed newly synthesized APP to its site of cleavage. In order to follow the intracellular trafficking of APP, we have designed a construct expressing the last 112 amino acids of APP with a photoactivatable GFP (paGFP) tag on the C-terminus (β APP-paGFP). Using 405nm light, we will photoactivate β APP-paGFP at the Golgi, and follow its trafficking and cleavage in downstream compartments. It is currently thought that APP is first delivered to the plasma membrane and subsequently endocytosed into endsomes and lysosomes. Surprisingly, we demonstrate that APP is rapidly delivered from the Golgi to lysosomes and cleaved in transiently transfected SN56 cells. Cells treated with inhibitors of lysosomal activity or specific inhibitors of γ -secretase lead to the accumulation of paGFP fluorescence at the lysosomal membrane. siRNA-mediated knockdown of AP-3, but not the related adaptor protein, AP-1, can disrupt the rapid and direct trafficking of APP. These results demonstrate a novel direct trafficking pathway for APP from the Golgi to the lysosome, and may lead to new therapeutic targets.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.011 | 0.009 |
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".