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Cited by 80Traumatic Brain Injury and Neurovascular DisturbancesNeuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatments

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

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Webster, Scott J., Van Eldik, Linda J., Watterson, D. Martin, Bachstetter, Adam D.·2015·The Journal of Neuroscience
DOI 10.1523/jneurosci.0291-15.2015PMC PMC4405562
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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.

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  • Many animal studies show increased production and accumulation of amyloid precursor protein (APP), Aβ, and pathological tau following TBI.

    “Second, many animal studies show increased production and accumulation of amyloid precursor protein (APP), Aβ, and pathological tau following TBI (16, 21–28).”

    From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [16]

    The Results section reports increased Aβ deposition after closed head injury in APP/PS1 mice and states that TBI can increase APP levels in mice. The Introduction reports changes in amyloid or tau pathology across animal studies, but the paper does not establish increased production of APP, Aβ, and tau or specifically show accumulation of pathological tau. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Numerous population-based studies demonstrate that head injury during adulthood increases the risk of AD later in life.

    “First, numerous population-based studies demonstrate that head injury during adulthood increases the risk of AD later in life (12–19)”

    From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [16]

    The Introduction (page not provided) says head injury is associated with increased risk of later-life dementia, including AD, and the Discussion cites epidemiological studies linking prior head injury to cognitive impairment and dementia. The paper does not specify injury during adulthood or establish that numerous population-based studies demonstrate a causal increase in AD risk. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • There is a direct relationship between neuroinflammation and functional recovery.

    “Collectively, these results indicate that there is a direct relationship between neuroinflammation and functional recovery”

    From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [16]

    The Discussion reports that inhibiting proinflammatory cytokine upregulation prevented chronic cognitive impairment after head injury in an Alzheimer-relevant mouse model, linking the neuroinflammatory response to neurological outcomes. That supports a relationship in this model, but not an unqualified, direct relationship with functional recovery generally. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • mRNA expression of CCR2, CD68, and MHC-II, characteristically expressed by macrophages, was delayed in APP/PS1 mice compared to wild-type controls following TBI.

    “In addition, mRNA expression of CCR2, CD68, and MHC-II, characteristically expressed by macrophages, was delayed in APP/PS1 mice compared to wild-type controls following TBI.”

    From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [16]

    The section on the temporal neuroinflammatory response (page unavailable) reports a CCR2 spike at one month, greatest in injured APP/PS1 mice, and CD68 and MHC-II peaks at seven days in that group. It does not establish that CCR2 expression was delayed relative to injured wild-type mice. It also describes CD68 and MHC-II as markers of microglia/macrophage activation, rather than characterizing all three markers as macrophage-specific. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • While both brain-injured AD and wild-type mice had increased expression of inflammatory cytokines IL-1β, IL-6, and TNFα, peak elevations were delayed by 7 days in the AD mice but persisted in conjunction with astrocyte activation.

    “While both brain-injured AD and wild-type mice had increased expression of inflammatory cytokines IL-1β, IL-6, and TNFα, peak elevations were delayed by 7 days in the AD mice but persisted in conjunction with astrocyte activation.”

    From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [16]

    The cytokine-response Results section reports that IL-1β, IL-6, and TNFα gene expression peaked at 7 days after injury in APP/PS1 mice, later than in wild-type mice. But cytokine protein levels followed similar time courses in both groups, and the chronic-time-point Results report no injury-related increase in those cytokines at day 32. Persistent activation is supported for astrocytes, not for sustained elevation of all three cytokines. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Webster, S. J., Van Eldik, L. J., Watterson, D. M., & Bachstetter, A. D.
Affiliations
  • Northwestern University (US)
  • University of Kentucky (US)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2015-04-22
Volume
35
Issue
16
Pages
6554-6569
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.0291-15.2015
PMC
PMC4405562
OpenAlex
W2128358339
Cited by
80
References
93
Citations by year
2026: 7 · 2025: 2 · 2024: 3 · 2022: 7 · 2021: 7 · 2020: 8 · 2019: 12 · 2018: 10 · 2017: 7 · 2016: 15 · 2015: 2
FWCI
7.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by)
Funders
  • Kentucky Spinal Cord and Head Injury Research Trust
  • National Institutes of Health
  • National Institute on Aging (K99AG044445)
  • National Institute of Neurological Disorders and Stroke (F32NS084605)
Topics
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
closed head injury, traumatic brain injury, Alzheimer's disease, neuroinflammation, chronic neuroinflammation, astrocytes, cytokines, chemokines, cognitive impairment, radial arm water maze
MeSH terms
Aging, Alzheimer Disease, Animals, Astrocytes, Brain Injuries, Cognition Disorders, Disease Models, Animal, Female, Male, Pyridazines, Pyrimidines, Cytokines, Head Injuries, Closed, Amyloid beta-Protein Precursor, Microglia, Disease Progression, Maze Learning, Inflammation Mediators, Chemokines, Mice, Gene Knock-In Techniques

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