Journal Article

DZNE-2026-00351

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Inflammasome adaptor ASC promotes sustained neuroinflammation and mild cognitive impairment in a closed-head injury model.

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

2026
ASCJ Ann Arbor, Mich.

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Please use a persistent id in citations: doi:10.1172/JCI199818

Abstract: Mild 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.

Keyword(s): Animals (MeSH) ; CARD Signaling Adaptor Proteins: genetics (MeSH) ; CARD Signaling Adaptor Proteins: metabolism (MeSH) ; Mice (MeSH) ; Cognitive Dysfunction: pathology (MeSH) ; Cognitive Dysfunction: metabolism (MeSH) ; Cognitive Dysfunction: genetics (MeSH) ; Cognitive Dysfunction: etiology (MeSH) ; Inflammasomes: genetics (MeSH) ; Inflammasomes: metabolism (MeSH) ; Disease Models, Animal (MeSH) ; Mice, Knockout (MeSH) ; Neuroinflammatory Diseases: pathology (MeSH) ; Neuroinflammatory Diseases: metabolism (MeSH) ; Neuroinflammatory Diseases: genetics (MeSH) ; Neuroinflammatory Diseases: etiology (MeSH) ; Male (MeSH) ; Brain Concussion: pathology (MeSH) ; Brain Concussion: genetics (MeSH) ; Brain Concussion: metabolism (MeSH) ; Microglia: pathology (MeSH) ; Microglia: metabolism (MeSH) ; Mice, Inbred C57BL (MeSH) ; Dementia ; Inflammation ; Innate immunity ; Neuroscience ; Transcriptomics ; CARD Signaling Adaptor Proteins ; Inflammasomes ; Pycard protein, mouse

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Contributing Institute(s):

1. Translational Biogerontology (AG Ehninger)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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