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 relationship between these conditions is not completely understood, but the conditions may share additive or synergistic pathological hallmarks that may serve as novel therapeutic targets. Heightened inflammasome signaling plays a critical role in the pathogenesis of central nervous system injury (CNS) and the release of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) speck from neurons and activated microglia contribute significantly to TBI and AD pathology. This study investigated whether inflammasome signaling after TBI was augmented in AD transgenic mice models and whether this signaling pathway impacted biochemical and neuropathological outcomes as well as overall cognitive function. There was a statistically significant increase in the levels of inflammasome signaling proteins caspase-1, caspase-8, ASC, and interleukin (IL)-1β after TBI in both wild type and 3xTg animals. At 1-day post injury, significant increases in ASC and IL-1β protein were measured in AD TBI mice compared to WT TBI. Behavioral testing showed that injured AD mice had altered cognitive function when compared to injured WT mice. Elevated Aβ was seen in the ipsilateral cortex and hippocampus of sham and injured AD when compared to respective groups at 12 weeks post injury along with brain volumetric loss in injured AD mice. Finally, treatment of injured AD mice with IC100, an anti-ASC monoclonal antibody, inhibited the inflammasome, as evidenced by reduced levels of IL-1β in the injured cortex at 1-week post injury. These findings show that the inflammasome response is heightened in mice genetically predisposed to AD and suggest that AD may exacerbate TBI pathology. Thus, dampening inflammasome signaling may offer a novel approach for the treatment of AD and TBI.