Peripheral macrophage infiltration and complement-initiation lead to synaptic loss and cognitive decline following traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a highly prevalent and extremely debilitating problem with nearly 2 million new cases reported annually and over 5 million individuals living with long-term injury-induced deficits. Critical changes that affect cognition take place over time following the initial insult and the innate immune system is a key mechanism that contributes to chronic neurodegeneration. Two at risk populations for TBI are adolescents and the elderly; two populations with vastly different immune parameters. In this work we compared injury-induced immune responses and cognitive decline from young and aged animals. In both young and aged animals significant increases in inflammatory responses in the brain were measured immediately following injury. In the aged animals, there are exacerbated and prolonged inflammatory responses, characterized by macrophage infiltration, microglia activation and robust cytokine/chemokine profiles. This exacerbated immune response corresponds with worsened cognitive decline in the aged animals. Furthermore, we found complement initiation (C1q, C3) increases corresponding with synapse loss in aged-injured animals. Complement initiation can lead to microglia mediated pruning in development and neurodegenerative disease. Thus we investigated if microglia and/or macrophages interacted with C1q in aged-injured animals. We measured co-localization between Iba-1, CD68 and C1q suggesting that these immune cells may be causing synaptic loss. Currently, we are testing if interference of these pathways (macrophage infiltration, microglia activation and/or complement initiation) can reverse injury-induced cognitive decline.