Astrocytes are becoming crucial players in the pathology of neurodegenerative disorders, such as Alzheimer’s disease (AD). Astrocyte responses have been mainly analyzed in the context of amyloid-beta (Abeta) pathology, highlighting their role in the development/progression of amyloidosis and their relationship with the microglial response. Regarding tau pathology, some studies have reported that astrocytes respond to hyperphosphorylated tau (phospho-tau) and suggested their implication on tau transmission/elimination. Here, we aimed to analyze the astroglial reactivity to tau pathology in the hippocampus of two transgenic mouse models of tauopathy, ThyTau22 and P301S. Proteinopathy was assessed by western-blotting and immunohistochemistry using phospho-tau antibodies (AT8). Inflammatory markers (GFAP, Iba-1, CD45, TREM2) were analyzed by qPCR and immunohistochemistry for bright-field microscopy; glial-phospho-tau relationship was analyzed under confocal and transmission electron microscopy. P301S mice exhibited an intense reactive astrogliosis, increasing with aging in parallel to a strong phospho-tau pathology. ThyTau22 model showed a slighter astrocyte reactivity accompanied by a lesser accumulation of phospho-tau. Astrogliosis in P301S mice closely correlated with an acute DAM-like microglial activation, not observed in ThyTau22 hippocampus. Confocal and ultrastructural studies revealed that, in both models, astrocytic processes contained phospho-tau, especially those surrounding blood vessels. Our results support that astrocytes respond to tau pathology in the absence of Abeta. This reactivity highly correlates with phospho-tau pathology and markedly depends on microglial activation. Moreover, astrocytes may play a role in the elimination/spreading of phospho-tau species through the brain. Deciphering the mechanisms underlying these processes might help to develop therapies to slow down the progression of AD.Supported by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union through grants PI18/01557 (to AG), PI18/01556 (to JV), and by Junta de Andalucia through Consejería de Economía y Conocimiento grants UMA18-FEDERJA-211 (AG), P18-RT-2233 (AG) and US-1262734 (JV) co-financed by Programa Operativo FEDER2014-2020.
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