Tau hyperphosphorylation favors the formation of neurofibrillary tangles and triggers the gradual loss of neuronal functions in tauopathies, including Alzheimer's disease. Herein, we demonstrated that chronic treatment with an inhibitor (J4) of equilibrative nucleoside transporter 1 (ENT1), which plays a critical role in controlling adenosine homeostasis and purine metabolism in the brain, exerted beneficial effects in a mouse model of tauopathy (Thy-Tau22, Tau22). Chronic treatment with J4 improved spatial memory deficits, mitochondrial dysfunction, synaptic plasticity impairment, and gliosis. Immunofluorescence assays showed that J4 not only reduced Tau hyperphosphorylation but also normalized the reduction in mitochondrial mass and suppressed the abnormal activation of AMP-activated protein kinase (AMPK), a pathogenic feature that is also observed in the brains of patients with tauopathies. Given that AMPK is an important energy sensor, our findings suggest that energy dysfunction is associated with tauopathy and that J4 may exert its protective effect by improving energy homeostasis. Bulk RNA-seq analysis revealed that J4 also mitigated immune signature associated with Tau pathology including C1q upregulation and A1 astrocyte markers. Collectively, our findings suggest that identifying strategies for normalizing energy and neuroimmune dysfunctions in tauopathies through adenosinergic signaling modulation may pave the way for the development of treatments for Alzheimer's disease.

中文翻译：

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新型平衡核苷转运蛋白1抑制剂可减轻Tau介导的神经变性

Tau蛋白的过度磷酸化促进了神经原纤维缠结的形成，并触发了包括阿尔茨海默氏病在内的多种疾病中神经元功能的逐渐丧失。本文中，我们证明了用平衡核苷转运蛋白1（ENT1）抑制剂（J4）进行的慢性治疗在控制脑内腺苷稳态和嘌呤代谢中起着关键作用，在tauopathy小鼠模型中发挥了有益作用（Thy- Tau22，Tau22）。长期用J4治疗可改善空间记忆障碍，线粒体功能障碍，突触可塑性损伤和神经胶质细胞增生。免疫荧光分析表明，J4不仅减少了Tau过度磷酸化，而且使线粒体质量的减少正常化，并抑制了AMP激活的蛋白激酶（AMPK）的异常激活，一种致病性特征，在患有tauopathies的患者的大脑中也观察到。鉴于AMPK是重要的能量传感器，我们的发现表明能量功能障碍与tauopathy有关，J4可能通过改善能量稳态来发挥其保护作用。大量RNA-seq分析显示，J4还减轻了与Tau病理学相关的免疫标记，包括C1q上调和A1星形胶质细胞标记。总体而言，我们的研究结果表明，通过腺苷能信号调节调节正常化能量和神经免疫功能障碍的策略可能为阿尔茨海默氏病的治疗方法铺平道路。我们的发现表明能量功能障碍与tauopathy有关，并且J4可能通过改善能量稳态来发挥其保护作用。大量RNA-seq分析显示，J4还减轻了与Tau病理学相关的免疫标记，包括C1q上调和A1星形胶质细胞标记。总体而言，我们的研究结果表明，通过腺苷能信号调节调节正常化能量和神经免疫功能障碍的策略可能为阿尔茨海默氏病的治疗方法铺平道路。我们的发现表明能量功能障碍与tauopathy有关，并且J4可能通过改善能量稳态来发挥其保护作用。大量RNA-seq分析显示，J4还减轻了与Tau病理学相关的免疫标记，包括C1q上调和A1星形胶质细胞标记。总体而言，我们的研究结果表明，通过腺苷能信号调节调节正常化能量和神经免疫功能障碍的策略可能为阿尔茨海默氏病的治疗方法铺平道路。