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

Li, T.; Castro-Gomez, S.; Botella Lucena, P.; Vieira-Saecker, A.; Schwartz, S.; Deng, Y.; Ding, Y.; Stein, V.; Latz, E.; Heneka, M. T.

doi:10.1101/2025.06.19.660521

bioRxiv · 10.1101/2025.06.19.660521

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

Li, T.·Castro-Gomez, S.·Botella Lucena, P.·Vieira-Saecker, A.·Schwartz, S.·Deng, Y.·Ding, Y.·Stein, V.·Latz, E.·Heneka, M. T.

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Abstract

Mild brain traumatic brain injury (mTBI) 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 in CHI models. Single-cell RNA sequencing of cortical tissue revealed selective expression of Pycard (PYD and CARD domain containing), also known as Asc (apoptosis-associated speck-like protein containing a caspase recruitment domain), which encodes the inflammasome adaptor ASC, predominantly in microglial clusters. Sustained upregulation of inflammasome-related proteins persisted up to 21 days in a model for mTBI, 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.

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Li, T., Castro-Gomez, S., Botella Lucena, P., Vieira-Saecker, A., Schwartz, S., Deng, Y., Ding, Y., Stein, V., Latz, E., Heneka, M. T.. 2025-06-25. ASC contributes to sustained glial reactivity and mild cognitive impairment after closed-head injury. https://doi.org/10.1101/2025.06.19.660521

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