title: Closed head injury in an age-related Alzheimer mouse model leads to an altered neuroinflammatory response and persistent cognitive impairment.
abstract: Epidemiological studies have associated increased risk of Alzheimer's disease (AD)-related clinical symptoms with a medical history of head injury. Currently, little is known about pathophysiology mechanisms linked to this association. Persistent neuroinflammation is one outcome observed in patients after a single head injury. Neuroinflammation is also present early in relevant brain regions during AD pathology progression. In addition, previous mechanistic studies in animal models link neuroinflammation as a contributor to neuropathology and cognitive impairment in traumatic brain injury (TBI) or AD-related models. Therefore, we explored the potential interplay of neuroinflammatory responses in TBI and AD by analysis of the temporal neuroinflammatory changes after TBI in an AD model, the APP/PS1 knock-in (KI) mouse. Discrete temporal aspects of astrocyte, cytokine, and chemokine responses in the injured KI mice were delayed compared with the injured wild-type mice, with a peak neuroinflammatory response in the injured KI mice occurring at 7 d after injury. The neuroinflammatory responses were more persistent in the injured KI mice, leading to a chronic neuroinflammation. At late time points after injury, KI mice exhibited a significant impairment in radial arm water maze performance compared with sham KI mice or injured wild-type mice. Intervention with a small-molecule experimental therapeutic (MW151) that selectively attenuates proinflammatory cytokine production yielded improved cognitive behavior outcomes, consistent with a link between neuroinflammatory responses and altered risk for AD-associated pathology changes with head injury.
authors.affiliation: Sanders-Brown Center on Aging.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Webster
authors.affiliation: Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky 40536, and.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Van Eldik
authors.affiliation: Department of Pharmacology, Northwestern University, Chicago, Illinois 60611.
authors.forename: D Martin
authors.identifier: http://orcid.org/0000-0001-7605-5866
authors.initials: DM
authors.lastname: Watterson
authors.affiliation: Sanders-Brown Center on Aging, adam.bachstetter@uky.edu.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Bachstetter
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000150:complications / Q000473:pathology* / Q000523:psychology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001930:Brain Injuries; D018925:Chemokines / Q000378:metabolism; D003072:Cognition Disorders / Q000150:complications / Q000473:pathology* / Q000503:physiopathology* / Q000523:psychology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D055879:Gene Knock-In Techniques; D016489:Head Injuries, Closed / Q000150:complications / Q000473:pathology* / Q000503:physiopathology / Q000523:psychology*; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D017628:Microglia / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology
chemical_list: C575875:2-(4-(4-methyl-6-phenylpyridazin-3-yl)piperazin-1-yl)pyrimidine; D016564:Amyloid beta-Protein Precursor; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D011724:Pyridazines; D011743:Pyrimidines
keywords: amyloid plaque; astrocytes; cytokines; microglia; neuroinflammation; traumatic brain injury