Traumatic brain injury (TBI) is extremely debilitating for the aging community with both increased incidence and outcome severity within this population. Furthermore, TBI is a strong environmental risk factor for development of Alzheimer's disease and other dementia related illnesses. The importance of age as a prognostic factor after TBI has long been recognized but limited studies have been devoted to understand mechanisms that regulate secondary events that occur after the initial trauma. Even less research has been aimed at studying the mechanisms of cognitive loss in the elderly. The critical changes that affect cognition take place over a long period of time following the initial insult and the innate immune system activation is a key secondary injury mechanism that contributes to chronic neurodegeneration and loss of neurological function. In this proposal we will investigate the respective contribution of infiltrating macrophages and activated resident microglia in production of a neurotoxic and inflammatory milieu as well as direct interactions with neuronal synapses following TBI in an aging animal. Preliminary data for this proposal has found that TBI causes an exacerbated and prolonged CCR2+ macrophage infiltration in the aging brain. The increased recruitment of peripherally derived monocytes significantly augments TBI-induced neuroinflammatory sequelae and is paralleled by an increased expression of the superoxide-generating enzyme NOX2 which may potentiate injury-induced cognitive dysfunction observed in old animals. All together these findings demonstrate that, in the aging brain, peripherally derived macrophages have a distinct contribution to the TBI-related inflammatory response. Based upon these observations we hypothesize that the robust infiltration of peripherally derived macrophages and the consequent inflammatory response is responsible for exacerbated loss of cognitive functions by decreasing dendritic spine density. In this proposal, we will identify the temporal relationships between macrophage infiltration/microglia activation and inflammatory profiles in an aging brain after injury. Furthermore, we will identify mechanistic links between macrophage infiltration and altered dendritic spine morphology. We will determine if TBI-induced cognitive deficits are a direct result of macrophage induced ROS production and/or inappropriate synaptic pruning. Finally, we will investigate if blockade of macrophage infiltration can mitigate injury-induced neurotoxicity thereby alleviating cognitive deficits. Findings from this work will advance mechanistic understanding of secondary mechanisms associated with TBI and test two pharmacological agents (already in clinical trials) for treatment of TBI-induced cognitive deficits in an aging animal.
Clinically, traumatic brain injury (TBI) is a strong environmental risk factor for the development of Alzheimer's disease and dementia and age is a significant factor in both the risk and the incidence of acquired brain injury. Neuroinflammation, defined as activation of brain resident microglia and infiltrating monocytes plays a pivotal role in chronic neurodegeneration and loss of neurological function. Our results demonstrate that in the aging brain, peripherally derived macrophages have a distinct contribution to the TBI-related inflammatory response. Based upon these observations we hypothesize that: the robust infiltration of peripherally derived macrophages and the consequent inflammatory response is responsible for exacerbated loss of cognitive functions by decreasing dendritic spine density. We will test this hypothesis by using innovative genetic models and pharmacological approaches; our long term goal is to understand the cellular mechanism/s underlying TBI- induced cognitive deficits in the aging brain in order to develop clinically relevant treatment strategies.
