Inflammasome Activation after Traumatic Brain Injury as a Risk Factor for Alzheimer’s Disease

Abstract

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). The relationships between these conditions are not completely understood and may share specific pathological and immunological hallmarks that could be additive or synergistic and represent novel therapeutic targets. 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 augments ADinduced biochemical and neuropathological outcomes using established AD-transgenic mouse models. 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). Mice were then sacrificed, and the ipsilateral cortex tissue processed for inflammasome protein expression by immunoblotting analysis. There was a statistically significant increase in inflammasome signaling proteins Caspase-1, Caspase-8, ASC, and IL-1b in controls and TBI in both wild type and transgenic animals. At 1 day post TBI, significant increases in ASC, Caspase-8 and IL-1b protein expression were observed in AD mice compared to wild type. These findings show that the inflammasome is involved in the regulation of the innate immune response after TBI in AD-transgenic mice. Finally, inflammasome signaling appears to play a key role in the course of AD pathophysiology after TBI and represents a promising target for therapeutic development for TBI and AD patient populations.