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

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 comprehen...

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Bibliographic Details
Published in:	Journal of neuroinflammation Vol. 21; no. 1; pp. 156 - 21
Main Authors:	Pybus, Alyssa F, Bitarafan, Sara, Brothers, Rowan O, Rohrer, Alivia, Khaitan, Arushi, Moctezuma, Felix Rivera, Udeshi, Kareena, Davies, Brae, Triplett, Sydney, Griffin, Martin N, Dammer, Eric B, Rangaraju, Srikant, Buckley, Erin M, Wood, Levi B
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 13-06-2024 BioMed Central BMC
Subjects:	Advertising executives Alzheimer Disease - genetics Alzheimer Disease - immunology Alzheimer Disease - metabolism Alzheimer Disease - pathology Alzheimer's disease Alzheimer’s pathology Analysis Animals Brain Brain - immunology Brain - metabolism Brain - pathology Brain Concussion - complications Brain Concussion - immunology Brain Concussion - metabolism Brain Concussion - pathology Cytokines Development and progression Disease Models, Animal Female Inflammation Injuries Male MAPK Mice Mice, Inbred C57BL Mice, Transgenic Mild traumatic brain injury Neuroimmunomodulation - physiology Neuroinflammation Neurons Paper industry Proteins Risk factors Sex Characteristics tau Proteins - genetics tau Proteins - metabolism Traumatic brain injury United States Mild traumatic brain injury Traumatic brain injury Cytokines Astrocyte reactivity Neuroinflammation 3xTg-AD Alzheimer’s pathology MAPK
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1742-2094 1742-2094
DOI:	10.1186/s12974-024-03128-1