祖父江 顕

Tau hyperphosphorylation has been considered a major contributor to neurodegeneration in Alzheimer's disease (AD) and frontotemporal dementia, and related tauopathies have gained prominence in the development of therapies for these conditions. Glial responses are key features of AD and frontotemporal dementia, and are associated with neuroinflammation. Numerous transgenic mouse models that recapitulate critical AD-like pathology and cognitive impairment have been developed to examine pathogenic mechanisms and evaluate therapeutic approaches targeting tau and glial reactivity. Glial reactivity and neuroinflammation coincide with tau hyperphosphorylation, which induces behavioral impairment; however, the specific correlation between glial cell activation and abnormal behavior remains unknown. In this study, we investigated changes in glial cell gene expressions related to abnormal behaviors in rTg4510 mice, which phenocopy the tau pathology, neuroinflammation, and neurodegeneration observed in human tauopathies. Both 4- and 6-month-old rTg4510 mice displayed significantly impaired nest-building 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 longer time in the open arms of the plus-maze test than control mice. Using a magnetic-activated cell-sorting technique, we analyzed glial cell gene expressions related to neuroinflammation, phagocytosis, and amyloid synthesis in the prefrontal cortex of rTg4510 mice. Regression analysis of glial gene expressions and behavioral tests revealed that various glial reactivities were associated with behavioral abnormalities. Our findings suggest specific genetic characteristics of glial cells that may lead to abnormal behavior in rTg4510 mice.

Systemic immune challenge can also cause neuropsychiatric abnormalities. Interferon-induced transmembrane protein 3 (IFITM3) plays a crucial role in cellular immune defense. Previously, we have demonstrated that IFITM3 affects neurodevelopment during the early developmental stage in mice, acting through innate immune activation. However, the pathophysiological significance of IFITM3 in immune system activation in adulthood remains unclear. To address this issue, we aimed to analyze the expression level of IFITM3 in the brain and the behavioral abnormalities in polyriboinosinic-polyribocytidylic acid (polyI:C)-treated adult male C57/BL6J wild-type (WT) and Ifitm3-/- mice. The expression levels of Ifitm3 mRNA and protein were significantly upregulated in the medial prefrontal cortex (mPFC), striatum, and hippocampus 24 h after polyI:C treatment in WT mice compared to saline-treated control mice. Furthermore, behavioral experiments revealed that polyI:C treatment induced cognitive dysfunction and anhedonia in WT mice, whereas Ifitm3-/- mice were resistant to these disorders. In conclusion, our results demonstrated that in adult mice, immune activation following polyI:C treatment may induce cognitive dysfunction and anhedonia through IFITM3 upregulation in the brain. These results suggest that IFITM3 is an attractive therapeutic target for neuropsychiatric dysfunction following immune activation in adulthood.

Alzheimer's disease (AD) is the leading neurodegenerative disease manifesting cognitive impairment. Its procession is regulated by activated glial cell-mediated neuroinflammation. Although estrogen deprivation is a known risk factor for AD in females, the impact of androgen deprivation on AD pathology in males, particularly regarding neuroinflammation, remains unclear. This study investigates the effects of long-term systemic androgen deprivation on AD pathology, including glial cell-specific gene expression, amyloid β (Aβ) pathology, and cognitive function in male castrated AppNL-G-F/NL-G-F (App) mice. We found significantly reduced androgen receptor (AR/Ar) expression levels in the precunei of male patients with early AD pathology and isolated brain microglia of male App mice compared with their nonpathological controls. In castrated App mice, microglial Tnf and Il6 and astrocytic Socs3 were downregulated, indicating that androgens may promote inflammation in the brain. However, Aβ accumulation and cognitive function were unaffected. These results suggest that although systemic androgen deprivation modulates neuroinflammation, the changes are insufficient to alter the AD phenotype or pathology in male App mice.