ASC contributes to sustained glial reactivity and mild cognitive impairment after closed-head injury

Mild brain trauma from closed-head injuries (CHI) can lead to prevalent neuropsychiatric disorders, including an increased risk for neurodegenerative diseases and dementia. Inflammasomes are molecular complexes crucial for neuroinflammation and secondary damage after trauma, however their role in mild CHI is poorly understood. In this study, we investigate the cellular expression of inflammasome-related genes and their functional significance after a CHI models. Analyzing single-cell RNA sequencing data from cortical cells from a model of CHI, we found that Pycard ( Asc ), the gene encoding for a common inflammasome adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), is expressed particularly in microglial clusters. Sustained upregulation of inflammasome-related proteins persisted up to 21 days in a model for mild CHI, with this pattern significantly reduced in Asc ^-/- mice. Importantly, mild cognitive impairment induced after mild CHI was largely abrogated in Asc ^-/- mice. These findings suggest that ASC, as the primary inflammasome adaptor, plays a critical role in sustaining neuroinflammation and contributes to cognitive deficits after mild CHI. This study provides insights into the molecular neuroinflammatory mechanisms underlying CHI, potentially informing future therapeutic strategies.