タウ病態モデルマウスにみられる行動異常とグリア細胞応答

抄録

Tau hyperphosphorylation has been considered a major contributor to neurodegeneration in Alzheimer’s disease and related tauopathies and has gained prominence in the development of therapies for Alzheimer’s disease. Neuroinflammation plays an important role in the progression of neurodegenerative disorders, and activated astrocytes and microglia strongly influence Aβ and tau pathologies. Numerous transgenic mouse models that recapitulate critical Alzheimer’s disease-like pathology have been developed to examine the pathogenic mechanisms underlying Alzheimer’s disease and evaluate therapeutic approaches targeting tau, but the relevant mechanisms remain unknown. In this study, we investigated changes in gene expression related to neuroinflammation in glial cells of rTg4510 mice, an animal model of non-Alzheimer’s disease tauopathy. First, we analyzed 4- and 6-month-old rTg4510 mice in terms of cognition and behaviors that mimic the behavioral and psychological problems of dementia. Deterioration of executive functions and impairment of daily life activities are early signs of Alzheimer’s disease. In the present study, nest-building behavior, which represents active interaction with the environment, evaluated the executive functions that are the basis of daily life activities. Both 4- and 6-month-old rTg4510 mice displayed significantly impaired nesting behavior compared with control mice. Moreover, rTg4510 mice of both age groups exhibited abnormal exploratory behavior, and these mice spent a greater amount of time in the open arm of the plus-maze test than control mice. We also used magnetic-activated cell sorting to analyze the expressions of genes related to neuroinflammation, phagocytosis, and amyloid synthesis in the prefrontal cortex of rTg4510 mice. Axl, Cd11c, and CD68 expression levels were increased in microglial cells, and H2-D1, Psmb8, and H2-T23 expression levels in astrocytes were also increased in 6-month-old rTg4510 mice compared with control mice. In conclusion, neuroinflammation may be related to neuronal degeneration and abnormal behavior in rTg4510 mice.