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J Neurosci. 2015 Apr 22;35(16):6554-69. doi: 10.1523/JNEUROSCI.0291-15.2015.

Closed head injury in an age-related Alzheimer mouse model leads to an altered neuroinflammatory response and persistent cognitive impairment.

Author information

1
Sanders-Brown Center on Aging.
2
Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky 40536, and.
3
Department of Pharmacology, Northwestern University, Chicago, Illinois 60611.
4
Sanders-Brown Center on Aging, adam.bachstetter@uky.edu.

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.

KEYWORDS:

amyloid plaque; astrocytes; cytokines; microglia; neuroinflammation; traumatic brain injury

PMID:
25904805
PMCID:
PMC4405562
DOI:
10.1523/JNEUROSCI.0291-15.2015
[Indexed for MEDLINE]
Free PMC Article

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