Alzheimer's Disease Leads to Chronic Pathological Changes and Inflammasome Signaling in an Animal Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) is a significant public health concern, often resulting in long-term impairments. TBI is also a known risk factor for Alzheimer's disease (AD), with both conditions sharing features such as inflammasome dysregulation. Inflammasome proteins are carried in extracellular vesicles (EVs) derived from blood plasma and serum. Our previous work showed that TBI in the context of AD acutely increases inflammasome activation and accelerates pathology. However, chronic effects of TBI in AD, particularly regarding sex differences, remain poorly characterized. Here, we used 3xTg-AD mice and wild-type (WT) controls, which underwent moderate controlled cortical impact (CCI) or sham surgery at 5 months of age. Mice were sacrificed at 3 months post-injury for biochemical and histopathological analysis. Cortical and hippocampal lysates were analyzed for inflammasome proteins and inflammatory cytokines via immunoblotting, while pathological markers were assessed using Ella Simple Plex technology and histopathology. In a separate cohort, 3xTg mice received moderate CCI and were sacrificed 7 days post-injury to evaluate sex differences. Cortical lysates were tested for pro-inflammatory cytokines and pathological markers via electrochemiluminescent immunoassay, and EVs were analyzed using mass spectrometry. AD-TBI mice showed increased expression of inflammasome proteins, pro-inflammatory cytokines, and glial fibrillary acidic protein (GFAP). TBI mice displayed elevated neurofilament light in the cortex, with both GFAP and neurofilament light co-localizing with inflammasome proteins in the perilesional cortex. Moreover, AD-TBI mice exhibited reduced cortical and hippocampal volumes compared to WT-TBI mice. In the sex differences cohort, EVs from male and female AD-TBI mice showed distinct patterns in upstream regulators and signaling pathways. Female-derived EVs showed greater activation of AD-related pathways. Sex-specific differences were also observed in cortical pro-inflammatory cytokine expression, although GFAP and amyloid-β levels were not significantly different between sexes. This study demonstrates that AD leads to changes in chronic inflammasome expression and neurodegenerative pathology, with marked sex-dependent differences in inflammatory and signaling responses in AD with TBI. These findings underscore the importance of considering both AD comorbidity and biological sex in the evaluation of TBI outcomes and therapeutic strategies.