Tau pathology is instrumental in the gradual loss of neuronal functions and cognitive decline in tauopathies, including Alzheimer’s disease (AD). Earlier reports showed that adenosine metabolism is abnormal in the brain of AD patients while consequences remained ill-defined. Herein, we aimed at investigating whether manipulation of adenosine tone would impact Tau pathology, associated molecular alterations and subsequent neurodegeneration. We demonstrated that treatment with an inhibitor (J4) of equilibrative nucleoside transporter 1 (ENT1) exerted beneficial effects in a mouse model of Tauopathy. Treatment with J4 not only reduced Tau hyperphosphorylation but also rescued memory deficits, mitochondrial dysfunction, synaptic loss, and abnormal expression of immune-related gene signatures. These beneficial effects were particularly ascribed to the ability of J4 to suppress the overactivation of AMPK (an energy reduction sensor), suggesting that normalization of energy dysfunction mitigates neuronal dysfunctions in Tauopathy. Collectively, these data highlight that targeting adenosine metabolism is a novel strategy for tauopathies.

中文翻译：

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平衡核苷转运蛋白 1 抑制可挽救 tau 蛋白病模型中的能量功能障碍和病理学


Tau蛋白病理学在tau蛋白病（包括阿尔茨海默病（AD））中神经元功能逐渐丧失和认知能力下降方面发挥着重要作用。此前的报道表明，AD 患者大脑中的腺苷代谢异常，但其后果仍不明确。在此，我们旨在研究腺苷张力的操纵是否会影响 Tau 病理学、相关分子改变和随后的神经变性。我们证明，平衡核苷转运蛋白 1 (ENT1) 抑制剂 (J4) 治疗对 Tau 病小鼠模型产生有益作用。 J4 治疗不仅减少了 Tau 过度磷酸化，还挽救了记忆缺陷、线粒体功能障碍、突触损失和免疫相关基因特征的异常表达。这些有益作用尤其归因于 J4 抑制 AMPK（一种能量减少传感器）过度激活的能力，表明能量功能障碍的正常化可以减轻 Tau 病中的神经元功能障碍。总的来说，这些数据强调了针对腺苷代谢是治疗 tau蛋白病的一种新策略。