INFLAMMASOME ACTIVATION AFTER TRAUMATIC BRAIN INJURY AS A RISK FACTOR FOR ALZHEIMER'S DISEASE

Abstract Background Traumatic Brain Injury (TBI) is a major cause of death and disability in the United States and a recognized risk factor for the development of Alzheimer’s disease (AD). Recent studies identified that heightened inflammasome signaling plays a critical role in the pathogenesis of CNS injury and that the release of apoptosis ‐associated speck‐like protein containing a caspase recruitment domain (ASC) specks from neurons and activated microglia contributes significantly to the detrimental innate immune inflammatory response. This study investigated whether inflammasome signaling after TBI augmented AD‐induced biochemical and neuropathological outcomes and loss of cognitive functionality using established AD‐transgenic mouse models. Method Five‐month‐old, 3xTg mice (with expressed APPswe, PS1M146V and tauP301L genes) and wild type controls were randomized and underwent moderate TBI controlled cortical impact (CCI) injury or served as controls. Animals were allowed to recover for 1 hour, 1 day, or 1 week after TBI (n = 5‐8/group) to assess acute pathology or were allowed to recover for 12 weeks (n = 10/group) in order to assess cognitive functionality and chronic pathology. At the end of the respective recovery periods, mice were sacrificed. The ipsilateral cortex tissue was processed for inflammasome protein expression by immunoblotting analysis. The chronic group was assessed for behavior utilizing open field (3 days), novel object recognition (2 weeks), and Morris water maze (6 weeks) testing after TBI. Result There was a statistically significant increase in the expression of inflammasome signaling proteins Caspase‐1, Caspase‐8, ASC, and IL‐1β in controls and TBI in both wild type and transgenic animals. Importantly, at 1 day after TBI, significant increases in ASC, Caspase‐8 and IL‐1β protein expression were observed in AD mice compared to wild type. In the chronic group, behavioral testing showed that injured mice had increased cognitive loss as indicated by decreased time in the center of the open field, and decreased time investigating the novel object. Conclusion These findings show that the inflammasome is involved in the regulation of the innate immune response after TBI in AD‐transgenic mice and that TBI acts as a potential accelerant of AD pathology.