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Caspase-1 inhibition improves cognition without significantly altering amyloid and inflammation in aged Alzheimer disease mice
Flores J, Fillion ML, LeBlanc AC.. Cell death & disease, 2022-10-11
Topic: Amyloid, tau and blood-test diagnosis
Human genetic and animal model studies indicate that brain microglial inflammation is a primary driver of cognitive impairment in Alzheimer Disease (AD). Inflammasome-activated Caspase-1 (Casp1) is associated with both AD microglial inflammation and neuronal degeneration. In mice, Casp1 genetic ablation or VX-765 small molecule inhibition of Casp1 given at onset of cognitive deficits strongly supports the association between microglial inflammation and cognitive impairment. Here, VX-765 significantly improved episodic and spatial memory impairment eight months after the onset of cognitive impairment in aged AD mice with significant amyloid beta peptide (Aβ) accumulation and microglial inflammation. Unexpectedly, while cognitive improvement was associated with dendritic spine density and hippocampal synaptophysin level recovery, VX-765 only slightly decreased Aβ deposition and did not alter biochemically-measured Aβ levels. Furthermore, increased hippocampal Iba1 + -microglia, GFAP + -astrocytes, IL-1β, and TNF-α levels were unaltered by VX-765. These results support the hypothesis that neuronal degeneration, not Aβ or microglial inflammation, drives cognitive impairment in AD.
Key findings
- Human genetic and animal model studies indicate that brain microglial inflammation is a primary driver of cognitive impairment in Alzheimer Disease (AD).
- Inflammasome-activated Caspase-1 (Casp1) is associated with both AD microglial inflammation and neuronal degeneration.
- Here, VX-765 significantly improved episodic and spatial memory impairment eight months after the onset of cognitive impairment in aged AD mice with significant amyloid beta peptide (Aβ) accumulation and microglial inflammation.
- Unexpectedly, while cognitive improvement was associated with dendritic spine density and hippocampal synaptophysin level recovery, VX-765 only slightly decreased Aβ deposition and did not alter biochemically-measured Aβ levels.
- These results support the hypothesis that neuronal degeneration, not Aβ or microglial inflammation, drives cognitive impairment in AD.
Why it matters
In aged Alzheimer disease mice, the Casp1 inhibitor VX-765 improved episodic and spatial memory even eight months after cognitive impairment began, and this improvement tracked with recovery of dendritic spine density and hippocampal synaptophysin. However, VX-765 only slightly decreased Aβ deposition, did not change biochemically measured Aβ levels, and did not alter microglial or astrocyte markers or IL-1β and TNF-α, so these animal findings point to neuronal degeneration rather than Aβ or inflammation as the driver of cognitive impairment.
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Study details
- Evidence strengthLow
How this study scored 42/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Cell death & disease) |
| Journal's citation record | 2 / 4 | Cell Death and Disease: journal h-index 233 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2022 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “mice”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 4 / 7 | Cited 42 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 7.0 citations a year over 6 year(s) since 2022 |
| Impact for its field and year | 2 / 6 | Cited 2.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 2 / 4 | Cited 33 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Andrea Claire LeBlanc: h-index 48 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | McGill University: institution h-index 1,373 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 36220815) |
| Free to read | 2 / 2 | Free to read |
| Total | 42 / 100 | — |
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Read the original
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Flores, J., Fillion, M. L., & LeBlanc, A. C. (2022). Caspase-1 inhibition improves cognition without significantly altering amyloid and inflammation in aged Alzheimer disease mice. Cell death & disease. https://doi.org/10.1038/s41419-022-05290-x
Vancouver
Flores J, Fillion ML, LeBlanc AC. Caspase-1 inhibition improves cognition without significantly altering amyloid and inflammation in aged Alzheimer disease mice. Cell death & disease. 2022. doi:10.1038/s41419-022-05290-x. PMID: 36220815.
BibTeX
@article{flores2022-36220815,
author = {Flores, J. and Fillion, M. L. and LeBlanc, A. C.},
title = {{Caspase-1 inhibition improves cognition without significantly altering amyloid and inflammation in aged Alzheimer disease mice}},
journal = {Cell death \& disease},
year = {2022},
doi = {10.1038/s41419-022-05290-x},
pmid = {36220815},
url = {https://doi.org/10.1038/s41419-022-05290-x}
}
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