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.
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This research was supported in part by National Institutes of Health/National Institute on Aging K99AG044445 to A.D.B., National Institutes of Health/National Institute of Neurological Disorders and Stroke F32 NS084605 to S.J.W., and the Kentucky Spinal Cord and Head Injury Research Trust 12-20A to L.J.V.E. We thank Danielle Goulding and Edgardo Dimayuga for assistance with various aspects of this work.
Webster, Scott J.; Van Eldik, Linda J.; Watterson, D. Martin; and Bachstetter, Adam D., "Closed Head Injury in an Age-Related Alzheimer Mouse Model Leads to an Altered Neuroinflammatory Response and Persistent Cognitive Impairment" (2015). Sanders-Brown Center on Aging Faculty Publications. 44.