P2RX7 inhibitor suppresses exosome secretion and disease phenotype in P301S tau transgenic mice

作者：Zhi Ruan, Jean-Christophe Delpech, Srinidhi Venkatesan Kalavai, Alicia A. Van Enoo, Jianqiao Hu, Seiko Ikezu, Tsuneya Ikezu · 发表于：Molecular Neurodegeneration · 年份：2020 · DOI：10.1186/s13024-020-00396-2 · 被引用次数：163 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Adenosine and Purinergic Signaling、Alzheimer's disease research and treatments

BACKGROUND: Neuronal accumulation of misfolded microtubule-associated protein tau is a hallmark of neuropathology in Alzheimer's disease, frontotemporal dementia, and other tauopathies, and has been a therapeutic target. Microglia can spread tau pathology by secreting tau-containing exosomes, although the specific molecular target is yet to be identified for the therapeutic intervention. P2X purinoceptor 7 (P2RX7) is an ATP-gated cation channel, enriched in microglia and triggers exosome secretion. The purpose of the study is to examine the therapeutic effect of an orally applicable, CNS-penetrant P2RX7 specific inhibitor on the early disease stage of a tauopathy mouse model. METHODS: Three-months-old P301S tau mice were treated with P2RX7-specific inhibitor GSK1482160 or vehicle for 30 days, followed by behavioral, biochemical and immunohistochemical assessment. GSK1482160 was also tested for exosome secretion from primary cultured murine astrocytes, neurons and microglia in vitro. RESULTS: tau and Tsg101 in hippocampal neurons, which was reduced by GSK1482160. On the other hand, GSK1482160 had no effect on microglial ramification or CD68 expression, which was significantly enhanced in P301S mice, or pro/anti-inflammatory cytokine gene expression. Strikingly, GSK1482160-treated P301S mice show significantly improved working and contextual memory as determined by Y-maze and fear conditioning tests. GSK1482160 also significantly increased accumulation of Tsg101 and CD81 in mic...