Bibliographic record
Abstract
The progression from proteolysis of the amyloid precursor protein (APP) to the formation of aggregated amyloid- peptide (A) deposits forms the basis of the amyloid hypothesis for the pathogenesis of Alzheimer disease. 1 Key steps in APP processing occur in subcellular compartments. Amyloid- is one of several end products that originate from the sequential proteolysis by -secretase and -secretase cleavage of the transmembrane APP. While A can range in size from 37 to 43 amino acids, it is the A 42 peptide that appears to be the foundation of fibrillar plaque formation in the brains of patients with Alzheimer disease. Alterations in the intracellular transport of APP can directly influence whether APP undergoes -secretase enzymatic activity, releasing a nontoxic peptide, -secretase-cleaved soluble APP (sAPP), or follows -secretase and -secretase enzymatic pathways, leading to generation of the neurotoxic forms of A. While the -secretase enzymes are found at the cell surface, -secretase lies within the Golgi apparatus and endosomes, the -secretase complex in the endoplasmic reticulum, lysosomes, and the cell surface. When APP is moved into the endosome, it is cleaved by -secretase and then transported either to the cell surface or to the lysosome to be further processed by -secretase to form A. However, when APP accumulates at the cell surface, it has a greater chance of interacting with -secretase to form nonamyloid-forming sAPP. SORL1 (also known as LR11 and SorLA) is 1 of several members of the low-density lipoprotein receptor family that interact and influence the cellular localization and processing of APP. SORL1 is a highly conserved type 1 receptor with vacuolar protein sorting and lowdensity lipoprotein-receptor class A and fibronectin domains. The low-density lipoproteinreceptor domain also serves as a binding site for apolipoprotein E. A single transmembrane domain carries a motif that specifically mediates SORL1 interaction with proteins involved in Golgi apparatus and endosome sorting of proteins, such as APP. An inherent modification in SORL1 enables it to control the clearance of some glycoproteins, modulate interactions with other proteins, and influence intracellular trafficking. 1 SORL1 and APP are colocalized within the perinuclear region of neurons and, when coexpressed in vitro, result in a complex formation in which there is SORL1-dependent translocation of APP.2 The active receptors for SORL1 are in the Golgi network as well as the endosome, further supporting an influential role in intracellular trafficking of APP. It has been suggested that SORL1 acts as a regulatory gate keeper for the amyloidogenic and nonamyloidogenic pathways, determining the ultimate destination for APP.2 , 3 When SORL1 effectively binds with APP, there is a reduction in sAPP and A, but when deficient, as in SORL1-knockout mice, the result is high levels of sAPP and A. 2 In a cell culture, Anderson et al 2 demonstrated that by increasing SORL1
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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) | 0.001 | 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 | 0.001 |
| 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".