title: Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease.
abstract: 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.
authors.affiliation: 1 Department of Neurosciences, Cleveland Clinic , Cleveland, Ohio.
authors.forename: Olga
authors.initials: O
authors.lastname: Kokiko-Cochran
authors.affiliation: 1 Department of Neurosciences, Cleveland Clinic , Cleveland, Ohio.
authors.forename: Lena
authors.initials: L
authors.lastname: Ransohoff
authors.affiliation: 1 Department of Neurosciences, Cleveland Clinic , Cleveland, Ohio.
authors.forename: Mike
authors.initials: M
authors.lastname: Veenstra
authors.affiliation: 1 Department of Neurosciences, Cleveland Clinic , Cleveland, Ohio.
authors.forename: Sungho
authors.initials: S
authors.lastname: Lee
authors.affiliation: 1 Department of Neurosciences, Cleveland Clinic , Cleveland, Ohio.
authors.forename: Maha
authors.initials: M
authors.lastname: Saber
authors.affiliation: 1 Department of Neurosciences, Cleveland Clinic , Cleveland, Ohio.
authors.forename: Matt
authors.initials: M
authors.lastname: Sikora
authors.affiliation: 1 Department of Neurosciences, Cleveland Clinic , Cleveland, Ohio.
authors.forename: Ryan
authors.initials: R
authors.lastname: Teknipp
authors.affiliation: 1 Department of Neurosciences, Cleveland Clinic , Cleveland, Ohio.
authors.forename: Guixiang
authors.initials: G
authors.lastname: Xu
authors.affiliation: 1 Department of Neurosciences, Cleveland Clinic , Cleveland, Ohio.
authors.forename: Shane
authors.initials: S
authors.lastname: Bemiller
authors.affiliation: 2 Department of Pharmaceutical Science, Northeast Ohio Medical University , Rootstown, Ohio.
authors.forename: Gina
authors.initials: G
authors.lastname: Wilson
authors.affiliation: 2 Department of Pharmaceutical Science, Northeast Ohio Medical University , Rootstown, Ohio.
authors.forename: Samuel
authors.initials: S
authors.lastname: Crish
authors.affiliation: 3 Department of Molecular Genetics Microbiology and Neurology, University of New Mexico , Albuquerque New Mexico.
authors.forename: Kiran
authors.initials: K
authors.lastname: Bhaskar
authors.affiliation: 1 Department of Neurosciences, Cleveland Clinic , Cleveland, Ohio.
authors.forename: Yu-Shang
authors.initials: YS
authors.lastname: Lee
authors.affiliation: 4 Biogen Idec , Cambridge, Massachusetts.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
authors.affiliation: 1 Department of Neurosciences, Cleveland Clinic , Cleveland, Ohio.|5 Department of Genetics and Department of Neurosciences, Case Western Reserve University , Cleveland, Ohio.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Lamb
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D000070642:Brain Injuries, Traumatic / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D016229:Amyloid beta-Peptides
keywords: Alzheimer's disease; macrophage; neuroinflammation; traumatic brain injury