Altered neuroinflammation and behavior following traumatic brain injury in a mouse model of Alzheimer's disease.
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Traumatic brain injury (TBI) has acute and chronic sequelae, including an increased risk for the development of Alzheimer's disease (AD). TBI-associated neuroinflammation is characterized by activation of brain-resident microglia and infiltration of monocytes; however, recent studies have implicated beta-amyloid as a major manipulator of the inflammatory response. To examine neuroinflammation following TBI and development of AD-like features, these studies examined the effects of TBI in the presence and absence of beta-amyloid. The R1.40 mouse model of cerebral amyloidosis was utilized, with a focus on time points well before robust AD pathologies. Unexpectedly, in R1.40 mice the acute neuroinflammatory response to TBI was strikingly muted, with reduced numbers of CNS myeloid cells acquiring a macrophage phenotype and decreased expression of inflammatory cytokines. At chronic time points, macrophage activation substantially declined in Non-Tg TBI mice; however, it was relatively unchanged in R1.40 TBI mice. The persistent inflammatory response coincided with significant tissue loss between 3 and 120 DPI in R1.40 TBI mice which was not observed in Non-Tg TBI mice. Surprisingly, inflammatory cytokine expression was enhanced in R1.40 mice compared to Non-Tg mice regardless of injury group. Although R1.40 TBI mice demonstrated task-specific deficits in cognition, overall functional recovery was similar to Non-Tg TBI mice. These findings suggest that accumulating beta-amyloid leads to an altered post-injury macrophage response at acute and chronic time points. Together, these studies emphasize the role of post-injury neuroinflammation in regulating long-term sequelae following TBI and also support recent studies implicating beta-amyloid as an immunomodulator.
