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Cited by 12Traumatic Brain Injury ResearchTraumatic Brain Injury and Neurovascular DisturbancesNeuroinflammation and Neurodegeneration Mechanisms

Profiling the neuroimmune cascade in 3xTg-AD mice exposed to successive mild traumatic brain injuries

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Pybus, Alyssa F., Bitarafan, Sara, Brothers, Rowan O., Rohrer, Alivia, Khaitan, Arushi, Moctezuma, Felix Rivera, Udeshi, Kareena, Davies, Brae +6 more·2024·Journal of Neuroinflammation
DOI 10.1186/s12974-024-03128-1PMC PMC11177462
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Abstract

Repetitive mild traumatic brain injuries (rmTBI) sustained within a window of vulnerability can result in long term cognitive deficits, depression, and eventual neurodegeneration associated with tau pathology, amyloid beta (Aβ) plaques, gliosis, and neuronal and functional loss. However, a comprehensive study relating acute changes in immune signaling and glial reactivity to neuronal changes and pathological markers after single and repetitive mTBIs is currently lacking. In the current study, we addressed the question of how repeated injuries affect the brain neuroimmune response in the acute phase of injury (< 24 h) by exposing the 3xTg-AD mouse model of tau and Aβ pathology to successive (1x-5x) once-daily weight drop closed-head injuries and quantifying immune markers, pathological markers, and transcriptional profiles at 30 min, 4 h, and 24 h after each injury. We used young adult 2–4 month old 3xTg-AD mice to model the effects of rmTBI in the absence of significant tau and Aβ pathology. We identified pronounced sexual dimorphism in this model, with females eliciting more diverse changes after injury compared to males. Specifically, females showed: (1) a single injury caused a decrease in neuron-enriched genes inversely correlated with inflammatory protein expression and an increase in AD-related genes within 24 h, (2) each injury significantly increased a group of cortical cytokines (IL-1α, IL-1β, IL-2, IL-9, IL-13, IL-17, KC) and MAPK phospho-proteins (phospho-Atf2, phospho-Mek1), several of which co-labeled with neurons and correlated with phospho-tau, and (3) repetitive injury caused increased expression of genes associated with astrocyte reactivity and macrophage-associated immune function. Collectively our data suggest that neurons respond to a single injury within 24 h, while other cell types, including astrocytes, transition to inflammatory phenotypes within days of repetitive injury.

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Cited by

Sorted by citations

Authors
Pybus, A. F., Bitarafan, S., Brothers, R. O., Rohrer, A., Khaitan, A., Moctezuma, F. R., Udeshi, K., Davies, B., Triplett, S., Griffin, M. N., Dammer, E. B., Rangaraju, S., Buckley, E. M., & Wood, L. B.
Affiliations
  • Georgia Institute of Technology (US)
  • Emory University (US)
  • Yale University (US)
Corresponding author
  • Buckley, Erin M.
  • Wood, Levi B.
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2024-06-13
Volume
21
Issue
1
Pages
156-156
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-024-03128-1
PMC
PMC11177462
OpenAlex
W4399626290
Cited by
12
References
135
Citations by year
2026: 9 · 2025: 3
FWCI
3.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Congressionally Directed Medical Research Programs (W81XWH-18-1-0669)
  • National Institutes of Health (1R01NS115994, 1R01AG075820)
Topics
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
repetitive mild traumatic brain injury, neuroimmune response, 3xTg-AD mice, Alzheimer's disease model, sex differences, cytokines, MAPK signaling, astrocyte activation, macrophages, tau phosphorylation, glial activation, gene expression profiling
MeSH terms
Alzheimer Disease, Animals, Brain, Brain Concussion, Disease Models, Animal, Female, Male, Mice, Inbred C57BL, Mice, Transgenic, Sex Characteristics, Neuroimmunomodulation, tau Proteins, Mice

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