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内容記述 |
Animal modeling of neurodegenerative disorders is essential for understanding causal mechanisms of neurodegeneration and development of therapeutic interventions. Tauopathy is one of major pathological hallmarks of neurodegenerative diseases. Since several mutations in tau gene were identified in FTDP-17, overexpression of familial mutant tau by transgenesis has been utilized to drive tauopathy and disease-relevant phenotypes. However, recent studies revealed that the transgenes disrupt the coding sequence of endogenous genes resulting deletions and/or structural variations at the insertion site (Goodwin et al. 2019). In this study, we utilized the knockin (KI) strategy to insert P301L mutated 1N4R human tau cDNA including the tetracycline response element (TRE) promoter into the Rosa26 safe harbor locus. To generate a human tau expressing mouse, the KI mouse was cross-bred with CaMKII-tTA transgenic mice under C57BL/6J background. The resultant mouse expresses P301L human tau in the forebrain with 4-fold of mouse tau in the absence of dentate granule neuronal degeneration, which was appeared in CaMKII-tTA transgenic mice under 129/Sv background (Han et al. 2012). Immunohistochemical and biochemical analyses revealed that tau pathologies were observed and extended in cerebral cortices and hippocampi of homozygous mice for P301L human tau gene from 12 months of age. In parallel with pathological tau progression, Iba1-positive microglia and GFAP-positive astrocytes were increased. As counterparts of microglial activation, homeostatic microglial markers, P2RY12 and Tmem119 were decreased in AT8 (p-tau specific antibody)-positive hippocampal regions. Significant correlations between AT8 signal and levels of microglial markers were observed in hippocampal regions of 12-15-month-old homozygous tau-KI mice. We further confirmed microglial activation in the hippocampus by immuno-staining of Axl, which is one of markers of disease associated microglia. In summary, the present mouse model shows spaciotemporal progressions of tau pathology and glial activation. This model will provide useful information of a linkage between p-tau-bearing neurons and activated microglia. Further examinations are ongoing for the elucidation of tau-induced neurotoxicity in association with neuroinflammation. |
