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

Scott J. Webster, Linda J. Van Eldik, D. Martin Watterson, Adam D. Bachstetter*

*Corresponding author for this work

Research output: Contribution to journalArticle

46 Scopus citations

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 duringAD 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.

Original languageEnglish (US)
Pages (from-to)6554-6569
Number of pages16
JournalJournal of Neuroscience
Volume35
Issue number16
DOIs
StatePublished - Apr 22 2015

Keywords

  • Amyloid plaque
  • Astrocytes
  • Cytokines
  • Microglia
  • Neuroinflammation
  • Traumatic brain injury

ASJC Scopus subject areas

  • Neuroscience(all)

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