Abstract
Increasing evidence demonstrates that aging influences the brain's response to traumatic brain injury (TBI), setting the stage for neurodegenerative pathology like Alzheimer's disease (AD). This topic is often dominated by discussions of post-injury aging and inflammation, which can diminish the consideration of those same factors before TBI. In fact, pre-TBI aging and inflammation may be just as critical in mediating outcomes. For example, elderly individuals suffer from the highest rates of TBI of all severities. Additionally, pre-injury immune challenges or stressors may alter pathology and outcome independent of age. The inflammatory response to TBI is malleable and influenced by previous, coincident, and subsequent immune insults. Therefore, pre-existing conditions that elicit or include an inflammatory response could substantially influence the brain's ability to respond to traumatic injury and ultimately affect chronic outcome. The purpose of this review is to detail how age-related cellular and molecular changes, as well as genetic risk variants for AD affect the neuroinflammatory response to TBI. First, we will review the sources and pathology of neuroinflammation following TBI. Then, we will highlight the significance of age-related, endogenous sources of inflammation, including changes in cytokine expression, reactive oxygen species processing, and mitochondrial function. Heightened focus is placed on the mitochondria as an integral link between inflammation and various genetic risk factors for AD. Together, this review will compile current clinical and experimental research to highlight how pre-existing inflammatory changes associated with infection and stress, aging, and genetic risk factors can alter response to TBI.
Highlights
Traumatic brain injury (TBI) is a growing healthcare burden worldwide
Inhibition of the receptor by dietary Colony stimulating factor-1 receptor (CSF1R) antagonists results in the depletion of up to 99% of all central nervous system (CNS) microglia, while animals are on the drug
This study found that increases in neuroinflammation-related proteins CD24, CD68, TLR4 and triggering receptor expressed on myeloid cells (TREM) 2, type-1 interferons, and chemokine-related transcripts observed in injured mice 7 days post injury were attenuated by microglia depletion
Summary
Pre-injury Neuroinflammation and Immune Stress Influence Traumatic Brain Injury Outcome. Increasing evidence demonstrates that aging influences the brain’s response to traumatic brain injury (TBI), setting the stage for neurodegenerative pathology like Alzheimer’s disease (AD). This topic is often dominated by discussions of post-injury aging and inflammation, which can diminish the consideration of those same factors before TBI. Pre-existing conditions that elicit or include an inflammatory response could substantially influence the brain’s ability to respond to traumatic injury and affect chronic outcome. This review will compile current clinical and experimental research to highlight how pre-existing inflammatory changes associated with infection and stress, aging, and genetic risk factors can alter response to TBI
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