Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease.

Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease.

Kokiko-Cochran Olga N; Ransohoff Lena; Veenstra Mike; Lee Sungho; Saber Maha; Sikora Matt; Teknipp Ryan; Xu Guixiang; Bemiller Shane M; Wilson Gina; Crish Samuel; Bhaskar Kiran; Lee Yu-Shang; Ransohoff Richard M; Lamb Bruce T

Journal of neurotrauma

2016

2016-04

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 after 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 used, 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 days post-injury 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 with 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 after TBI and also support recent studies implicating beta-amyloid as an immunomodulator.

Alzheimer Disease/etiology/*metabolism/pathology; Alzheimer's disease; Amyloid beta-Peptides/*metabolism; Animal; Animal/physiology; Animals; Behavior; Blotting; Brain Injuries; Brain/*metabolism/pathology; Disease Models; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Humans; Immunohistochemistry; Inbred C57BL; Inflammation/*metabolism/pathology; macrophage; Mice; neuroinflammation; Transgenic; traumatic brain injury; Traumatic/complications/*metabolism/*pathology; Western

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625–640

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