Bibliographic record
Abstract
Prion disease research has opened up the "black-box" of neurodegeneration, defining a key role for protein misfolding wherein a predominantly alpha-helical precursor protein, PrP (C), is converted to a disease-associated, β-sheet enriched isoform called PrP (Sc). In Alzheimer disease (AD) the Aβ peptide derived from the β-amyloid precuror protein APP folds in β-sheet amyloid. Early thoughts along the lines of overlap may have been on target, (1) but were eclipsed by a simultaneous (but now anachronistic) controversy over the role of PrP (Sc) in prion diseases. (2) (,) (3) Nonetheless, as prion diseases such as Creutzfeldt-Jakob Disease (CJD) are themselves rare and can include an overt infectious mode of transmission, and as familial prion diseases and familial AD involve different genes, an observer might reasonably have concluded that prion research could occasionally catalyze ideas in AD, but could never provide concrete overlaps at the mechanistic level. Surprisingly, albeit a decade or three down the road, several prion/AD commonalities can be found within the contemporary literature. One important prion/AD overlap concerns seeded spread of Aβ aggregates by intracerebral inoculation much like prions, (4) and, with a neuron-to-neuron 'spreading' also reported for pathologic forms of other misfolded proteins, Tau (5) (,) (6) and α-synuclein in the case of Parkinson Disease. (7) (,) (8) The concept of seeded spread has been discussed extensively elsewhere, sometimes under the rubric of "prionoids" (9), and lies outside the scope of this particular review where we will focus upon PrP (C). From this point the story can now be subdivided into four strands of investigation: (1) pathologic effects of Aβ can be mediated by binding to PrP (C), (10) (2) the positioning of endoproteolytic processing events of APP by pathologic (β-cleavage + γ-cleavage) and non-pathologic (α-cleavage + γ-cleavage) secretase pathways is paralleled by seemingly analogous α- and β-like cleavage of PrP (C) (Fig. 1) (3) similar lipid raft environments for PrP (C) and APP processing machinery, (11) (-) (13) and perhaps in consequence, overlaps in repertoire of the PrP (C) and APP protein interactors ("interactomes"), (14) (,) (15) and (4) rare kindreds with mixed AD and prion pathologies. (16) Here we discuss confounds, consensus and conflict associated with parameters that apply to these experimental settings.
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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 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.005 |
| Scholarly communication | 0.003 | 0.006 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.009 | 0.002 |
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".