engLi, TaoCastro-Gomez, Mario SergioLatz, EickeHeneka, Michael TBotella Lucena, PabloVieira-Saecker, AnaSchwartz, StephanieDing, YingyingDeng, YushuangGou, MalingStein, ValentinGolenbock, Douglas TInflammasome adaptor ASC promotes sustained neuroinflammation and mild cognitive impairment in a closed-head injury model.info:eu-repo/classification/ddc/610AnimalsCARD Signaling Adaptor Proteins: geneticsCARD Signaling Adaptor Proteins: metabolismMiceCognitive Dysfunction: pathologyCognitive Dysfunction: metabolismCognitive Dysfunction: geneticsCognitive Dysfunction: etiologyInflammasomes: geneticsInflammasomes: metabolismDisease Models, AnimalMice, KnockoutNeuroinflammatory Diseases: pathologyNeuroinflammatory Diseases: metabolismNeuroinflammatory Diseases: geneticsNeuroinflammatory Diseases: etiologyMaleBrain Concussion: pathologyBrain Concussion: geneticsBrain Concussion: metabolismMicroglia: pathologyMicroglia: metabolismMice, Inbred C57BLDementiaInflammationInnate immunityNeuroscienceTranscriptomicsCARD Signaling Adaptor ProteinsInflammasomesPycard protein, mouseMild traumatic brain injury (mTBI) from a closed-head injury (CHI) can lead to prevalent neuropsychiatric disorders, including mood disorders and 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 (mCHI) 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-seq analysis of cortical tissue after trauma revealed selective expression of Asc (also known as Pycard), which encodes the inflammasome adaptor apoptosis-associated Speck-like protein containing a caspase recruitment domain (ASC), predominantly in microglial clusters. Sustained upregulation of inflammasome-related proteins, microglia activation, and astrocyte reactivity persisted up to 21 days in a model for mTBI, with significant reduction of this pattern in Asc-/- mice. Importantly, mild cognitive impairment induced after mCHI 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 mCHI. This study provides insights into the molecular neuroinflammatory mechanisms underlying CHI, potentially informing future therapeutic strategies.The journal of clinical investigation 136(7), e199818 (2026). doi:10.1172/JCI199818info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionASCJ2026info:eu-repo/semantics/closedAccessDEhttps://pub.dzne.de/record/285815https://pub.dzne.de/search?p=id:%22DZNE-2026-00351%22Researchersinfo:eu-repo/semantics/altIdentifier/issn/0021-9738info:eu-repo/semantics/altIdentifier/pmid/pmid:41734021info:eu-repo/semantics/altIdentifier/issn/1558-8238info:eu-repo/semantics/altIdentifier/doi/10.1172/JCI199818