P3‐414: Evaluation of a novel caspase‐6 inhibitor as a potential treatment for Alzheimer's disease
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
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.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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 | 0.000 |
| 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 it