TY  - JOUR
AU  - Li, Tao
AU  - Castro-Gomez, Mario Sergio
AU  - Botella Lucena, Pablo
AU  - Vieira-Saecker, Ana
AU  - Schwartz, Stephanie
AU  - Ding, Yingying
AU  - Deng, Yushuang
AU  - Gou, Maling
AU  - Stein, Valentin
AU  - Golenbock, Douglas T
AU  - Latz, Eicke
AU  - Heneka, Michael T
TI  - Inflammasome adaptor ASC promotes sustained neuroinflammation and mild cognitive impairment in a closed-head injury model.
JO  - The journal of clinical investigation
VL  - 136
IS  - 7
SN  - 0021-9738
CY  - Ann Arbor, Mich.
PB  - ASCJ
M1  - DZNE-2026-00351
SP  - e199818
PY  - 2026
AB  - 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.
KW  - Animals
KW  - CARD Signaling Adaptor Proteins: genetics
KW  - CARD Signaling Adaptor Proteins: metabolism
KW  - Mice
KW  - Cognitive Dysfunction: pathology
KW  - Cognitive Dysfunction: metabolism
KW  - Cognitive Dysfunction: genetics
KW  - Cognitive Dysfunction: etiology
KW  - Inflammasomes: genetics
KW  - Inflammasomes: metabolism
KW  - Disease Models, Animal
KW  - Mice, Knockout
KW  - Neuroinflammatory Diseases: pathology
KW  - Neuroinflammatory Diseases: metabolism
KW  - Neuroinflammatory Diseases: genetics
KW  - Neuroinflammatory Diseases: etiology
KW  - Male
KW  - Brain Concussion: pathology
KW  - Brain Concussion: genetics
KW  - Brain Concussion: metabolism
KW  - Microglia: pathology
KW  - Microglia: metabolism
KW  - Mice, Inbred C57BL
KW  - Dementia (Other)
KW  - Inflammation (Other)
KW  - Innate immunity (Other)
KW  - Neuroscience (Other)
KW  - Transcriptomics (Other)
KW  - CARD Signaling Adaptor Proteins (NLM Chemicals)
KW  - Inflammasomes (NLM Chemicals)
KW  - Pycard protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41734021
C2  - pmc:PMC13038205
DO  - DOI:10.1172/JCI199818
UR  - https://pub.dzne.de/record/285815
ER  -