Age-related neuroimmune mechanisms responsible for trauma-induced chronic deficits
Karen Krukowski1,2, Austin Chou1,2, Xi Feng1,2, Elma Frias1,2, Brice Tiret2, Maria-Serena Palladini1,2, Lara-Kirstie Riparip1,2, Katherine Grue1,2, Caroline Guglielmetti2, Myriam Chaumeil2, and Susanna Rosi1,2,3
Brain and Spinal Injury Center1, Physical Therapy and Rehabilitation2, Neurological Surgery3, University of California San Francisco, San Francisco, CA
Traumatic brain injury (TBI) is extremely debilitating for the aging community with both increased incidence and outcome severity within this population. Furthermore, TBI is the most predictive environmental factor for development of Alzheimer's disease and other dementia related illnesses. Critical changes that affect cognition take place over time following the initial insult and previous work has identified the immune system to be a key mechanism that contributes to chronic neurodegeneration. We investigated the injury-induced cellular and molecular changes that lead to chronic cognitive deficits in aged animals. Using a focal trauma model we investigated learning and memory deficits chronically after injury (one month post). Aged-injured animals were impaired in both recognition and spatial memory when compared to age-matched sham animals. Furthermore, cognitive deficits were exacerbated when compared to young animals. Next, we investigated potential age-related neuroimmune mechanisms responsible for these deficits. We measured prolonged inflammatory responses, characterized by microglia activation and robust cytokine/chemokine profiles. We identified increases in complement initiation (C1q, C3), a newly identified regulator of microglia-synapse interactions. Specifically, we found accumulation of C1q on hippocampal synapse and increased C1q cognate receptor expression on microglia in the aged injured animals. These increases in C1q were paralleled with loss of hippocampal synapse at one-month post injury suggesting that microglia activation leads to chronic synapse loss in aged animals after trauma. Finally, we investigate the therapeutic potential of interference with this pathway for reversal of chronic trauma-induced deficits. For the first time, we identify that blockade of C1q reverses trauma-induced memory deficits in aged animals. Thus, therapeutically targeting the complement cascade early after trauma may provide a new avenue of clinical intervention following TBI in the aging population.