P3‐414: Evaluation of a novel caspase‐6 inhibitor as a potential treatment for Alzheimer's disease
Bibliographic record
Abstract
Caspase-6 activity is found abundantly in the neuropil threads, neuritic plaques and neurofibrillary tangles of familial and sporadic forms of Alzheimer disease. Caspase-6 induces axonal degeneration and memory impairment in mice (abstract submitted at this meeting). Therefore, inhibiting Caspase-6 represents a potential treatment for Alzheimer disease. Unfortunately, there are no known natural inhibitors of Caspase-6. In this study, we investigated a newly developed irreversible Caspase-6 inhibitor called NWL-117 developed by New World Laboratories. The toxicity of the Caspase-6 inhibitor was verified on the HCT116 cell line and human primary neurons by MTT, propidium iodide FACS analyses, and Caspase-3 processing by western blots or activity by fluorogenic assays. Dose-dependent inhibition of Caspase-6 was assessed by in vitro fluorogenic assays with purified recombinant active Caspase-6 and on HCT116 cells transfected with a self-activating form of Caspase-6. Inhibition of active Caspase-6 was also assessed in primary human neurons in culture. Caspase-6 activity in cellulo was assessed with FLICA TM -Caspase-6 assays. Specificity of the NWL-117 inhibitor for Caspase-6 was investigated by conducting dose response curves on other purified recombinant caspases by fluorogenic assays. The NWL-117 was not toxic to the HCT116 cells or the neurons at 20 to 100 μM concentrations. In vitro, a dose dependent inhibition of recombinant active Caspase-6 was observed between 50 nM (50%) and 5 μM (100%). NWL-117 was more potent than the peptide inhibitor, Ac-VEID-fmk. A 1 μM concentration of NWL-117 inhibited almost 50% of active Caspase-6 in HCT116 cells and showed a dose-dependent inhibition between 5 μM and 100 μM concentrations. Western blot analyses showed that the Caspase-6 was processed into its active form in the absence or presence of the inhibitor. These results show that NWL-117 is cell permeable and non-toxic at high concentrations. NWL-117 is a potent inhibitor of the processed active form of Caspase-6. Therefore, the NWL-117 can be used to assess if Caspase-6-mediated axonal degeneration can be inhibited and possibly reversed in primary human neurons and mouse brains. If so, this compound is an interesting “lead” compound to develop as an inhibitor of Caspase-6 in Alzheimer disease patients.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".