GLIA RESPONSES ARE ASSOCIATED WITH ABNORMAL BEHAVIORS IN AN ANIMAL MODEL OF TAU PATHOLOGIES

Abstract 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. Glia responses are key feature of AD and are associated with neuroinflammation. 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 and glial reactivity, 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. We first analyzed the behaviors of rTg4510 mice at 4- and 6-month-old that mimic behavioral and psychological problems of dementia. By using a magnetic-activated cell sorting technique, we then analyzed the gene expression related to neuroinflammation, phagocytosis, and amyloid synthesis in the prefrontal cortex of rTg4510 mice. Both 4- and 6-month-old rTg4510 mice displayed significantly impaired nesting behavior compared with control mice. Paired association learning was also impaired in 4-month-old rTg4510 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. In rTg4510 mice, Axl, Cd11c, and CD68 expression levels were increased in the microglial cells, and H2-D1, Psmb8, and H2-T23 expression levels in astrocyte cells were also increased when mice reached 6 months compared with control mice. These results raise a possibility that glia responses in rTg4510 mice may be related to their abnormal behavior.