INTRODUCTIONThe pathogenesis of two major pathogenic characters—amyloid beta (Aβ) accumulation and hyperphosphorylated tau protein—in the brains of patients with Alzheimer's disease (AD) remains unclear.METHODSWestern blot and immunofluorescence staining were performed to detect the proteins in the brains of Thorase conditional knockout/transgenic mice and their littermates. A co‐immunoprecipitation assay was applied to examine the Thorase‐interacting proteins.RESULTSGenetic deletion of Thorase resulted in tau hyperphosphorylation and promoted Aβ accumulation in the mouse brain. Conversely, Thorase overexpression alleviated the pathogenesis of AD. Thorase regulated the phosphorylation of tau by targeting specific kinases and theprotein phosphatase 2B (PP2B). Thorase deficiency also impaired microglial phagocytosis and induced neuroinflammation by the activation of the NOD‐like receptor thermal protein domain associated protein 3 (NLRP3) inflammasomes in microglia.DISCUSSIONThorase may be a potential druggable target for developing therapeutic approaches to treat AD and other neurodegenerative diseases.Highlights Thorase deletion leads to elevated amyloid beta (Aβ) deposition and hyperphosphorylated tau accumulation in the brain. Thorase regulates the phosphorylation of tau protein via PP2B. Thorase deficiency impairs microglial phagocytosis and promotesNLRP3‐mediated neuroinflammation. Overexpression of Thorase alleviates Aβ deposition and tau phosphorylation in the AD mouse model.

中文翻译：

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索拉酶缺乏导致小鼠大脑中 Aβ 积累和 tau 过度磷酸化


引言阿尔茨海默病 （AD） 患者大脑中两个主要致病特征——β 淀粉样蛋白 （Aβ） 积累和过度磷酸化的 tau 蛋白——的发病机制尚不清楚。方法进行 Thorase 条件性敲除/转基因小鼠及其同窝小鼠大脑中的蛋白质检测。应用免疫共沉淀测定法检测 Thorase 相互作用蛋白。结果Thorase 的基因缺失导致 tau 过度磷酸化并促进 Aβ 在小鼠脑中的积累。相反，Thorase 过表达减轻了 AD 的发病机制。Thorase 通过靶向特异性激酶和蛋白磷酸酶 2B （PP2B） 来调节 tau 的磷酸化。索酶缺乏还损害了小胶质细胞吞噬作用，并通过激活小胶质细胞中的 NOD 样受体热蛋白结构域相关蛋白 3 （NLRP3） 炎性小体诱导神经炎症。讨论 Horase 可能是开发治疗 AD 和其他神经退行性疾病的治疗方法的潜在成药靶点。亮点 Thorase 缺失导致 β 淀粉样蛋白 （Aβ） 沉积升高和大脑中过度磷酸化的 tau 积累。Thorase 通过 PP2B 调节 tau 蛋白的磷酸化。索酶缺乏症损害小胶质细胞吞噬作用并促进 NLRP3 介导的神经炎症。Thorase 的过表达减轻了 AD 小鼠模型中的 Aβ 沉积和 tau 磷酸化。