P2‐512: Identifying endogenous anti‐amyloid compounds
Bibliographic record
Abstract
Since peptide sequences other than ß-amyloid are susceptible to aggregation (the “amylome”), there is evolutionary pressure to inhibit deleterious protein-misfolding; accordingly, it is reasonable to postulate the existence of endogenous anti-aggregation molecules that could arrest the neurotoxic cascade of AD. From the Aß perspective, compounds binding to the EVHHQKLVFF basic residues of Aß could in principle interrupt glycosaminoglycan/ß-amyloid interactions, inhibiting neurotoxic aggregation. Searching for an “endogenous anti-AD compound” represents an unexplored concept in AD therapeutics design. An in silico to in vitro approach was employed. We created a comprehensive in silico library of 1,450 molecules (molecular weight less than 600 g/mol) that are endogenous to the human brain. These compounds were then screened in silico, using a molecular mechanics/molecular dynamics approach, for ability to bind to the EVHHQKLVFF region of Aß. Compounds identified in this in silico screen were then experimentally evaluated using in vitro assays (ThT, CD, MTT cell viability, EM aggregation) to assess their capacity to inhibit Aß aggregation and related neurotoxicity. To identify an endogenous anti-protein-misfolding compound, we devised a computational model of non-neurotoxic, unaggregated Aß; next, we devised an in silico strategy to screen a library of endogenous compounds for molecules capable of binding Aß's HHQK/BBXB domain. This identified a family of L-phosposerine metabolites as endogenous anti-aggregants. We next performed in vitro assays to assess the capacity of these compounds to inhibit Aß aggregation. L-phosphoserine was able to block Aß aggregation in a Thioflavin-T aggregation assay (IC-50 = 3.4 micromolar); to prevent Aß conformational change from helix to ß-sheet in circular dichroism studies; to bind to Aß (at HHQK) in mass spectrometry and NMR studies; to prevent Aß aggregation in electron microscopy studies; and to prevent Aß cellular toxicity in an (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay. Therefore, L-phosphoserine is an endogenous Aß anti-aggregant. An in silico screening strategy has identified a class of endogenous compounds that is able to inhibit Aß aggregation in vitro. Significantly, it is also known that L-phosphoserine neurochemistry is abnormal in AD patients; e.g. L-phosphoserine is one of the neural phosphomonoesters that is elevated in Alzheimer's disease brain.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".