| First Author | Flores J | Year | 2022 |
| Journal | Cell Death Dis | Volume | 13 |
| Issue | 10 | Pages | 864 |
| PubMed ID | 36220815 | Mgi Jnum | J:330039 |
| Mgi Id | MGI:7355245 | Doi | 10.1038/s41419-022-05290-x |
| Citation | Flores J, et al. (2022) Caspase-1 inhibition improves cognition without significantly altering amyloid and inflammation in aged Alzheimer disease mice. Cell Death Dis 13(10):864 |
| abstractText | 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 (Abeta) accumulation and microglial inflammation. Unexpectedly, while cognitive improvement was associated with dendritic spine density and hippocampal synaptophysin level recovery, VX-765 only slightly decreased Abeta deposition and did not alter biochemically-measured Abeta levels. Furthermore, increased hippocampal Iba1(+)-microglia, GFAP(+)-astrocytes, IL-1beta, and TNF-alpha levels were unaltered by VX-765. These results support the hypothesis that neuronal degeneration, not Abeta or microglial inflammation, drives cognitive impairment in AD. |
