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J Neuroinflammation ; 21(1): 130, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750510

RESUMO

Epidemiological studies have unveiled a robust link between exposure to repetitive mild traumatic brain injury (r-mTBI) and elevated susceptibility to develop neurodegenerative disorders, notably chronic traumatic encephalopathy (CTE). The pathogenic lesion in CTE cases is characterized by the accumulation of hyperphosphorylated tau in neurons around small cerebral blood vessels which can be accompanied by astrocytes that contain phosphorylated tau, the latter termed tau astrogliopathy. However, the contribution of tau astrogliopathy to the pathobiology and functional consequences of r-mTBI/CTE or whether it is merely a consequence of aging remains unclear. We addressed these pivotal questions by utilizing a mouse model harboring tau-bearing astrocytes, GFAPP301L mice, subjected to our r-mTBI paradigm. Despite the fact that r-mTBI did not exacerbate tau astrogliopathy or general tauopathy, it increased phosphorylated tau in the area underneath the impact site. Additionally, gene ontology analysis of tau-bearing astrocytes following r-mTBI revealed profound alterations in key biological processes including immunological and mitochondrial bioenergetics. Moreover, gene array analysis of microdissected astrocytes accrued from stage IV CTE human brains revealed an immunosuppressed astroglial phenotype similar to tau-bearing astrocytes in the GFAPP301L model. Additionally, hippocampal reduction of proteins involved in water transport (AQP4) and glutamate homeostasis (GLT1) was found in the mouse model of tau astrogliopathy. Collectively, these findings reveal the importance of understanding tau astrogliopathy and its role in astroglial pathobiology under normal circumstances and following r-mTBI. The identified mechanisms using this GFAPP301L model may suggest targets for therapeutic interventions in r-mTBI pathogenesis in the context of CTE.


Assuntos
Aquaporina 4 , Astrócitos , Transportador 2 de Aminoácido Excitatório , Camundongos Transgênicos , Tauopatias , Proteínas tau , Astrócitos/metabolismo , Astrócitos/patologia , Animais , Camundongos , Proteínas tau/metabolismo , Proteínas tau/genética , Aquaporina 4/metabolismo , Aquaporina 4/genética , Tauopatias/metabolismo , Tauopatias/patologia , Tauopatias/genética , Humanos , Transportador 2 de Aminoácido Excitatório/metabolismo , Transportador 2 de Aminoácido Excitatório/genética , Transportador 2 de Aminoácido Excitatório/biossíntese , Concussão Encefálica/metabolismo , Concussão Encefálica/patologia , Masculino , Fenótipo , Camundongos Endogâmicos C57BL
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