Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer’s disease (AD), with recent proteomic studies highlighting disrupted glial metabolism in AD. We report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN), rescues hippocampal memory function in mouse preclinical models of AD by restoring astrocyte metabolism. Activation of astrocytic IDO1 by amyloid β and tau oligomers increases KYN and suppresses glycolysis in an aryl hydrocarbon receptor–dependent manner. In amyloid and tau models, IDO1 inhibition improves hippocampal glucose metabolism and rescues hippocampal long-term potentiation in a monocarboxylate transporter–dependent manner. In astrocytic and neuronal cocultures from AD subjects, IDO1 inhibition improved astrocytic production of lactate and uptake by neurons. Thus, IDO1 inhibitors presently developed for cancer might be repurposed for treatment of AD.

中文翻译：

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恢复海马葡萄糖代谢可挽救阿尔茨海默氏病病理的认知


大脑葡萄糖代谢受损是阿尔茨海默病 (AD) 的一个病理特征，最近的蛋白质组学研究强调了 AD 中神经胶质代谢的破坏。我们报道，抑制吲哚胺-2,3-双加氧酶 1 (IDO1)（将色氨酸代谢为犬尿氨酸 (KYN)）可通过恢复星形胶质细胞代谢来挽救 AD 小鼠临床前模型中的海马记忆功能。 β淀粉样蛋白和 tau 寡聚体激活星形细胞 IDO1，以芳基烃受体依赖性方式增加 KYN 并抑制糖酵解。在淀粉样蛋白和 tau 蛋白模型中，IDO1 抑制可改善海马葡萄糖代谢，并以单羧酸转运蛋白依赖性方式挽救海马长时程增强。在 AD 受试者的星形胶质细胞和神经元共培养物中，IDO1 抑制改善了星形胶质细胞的乳酸生成和神经元的吸收。因此，目前开发的用于癌症的 IDO1 抑制剂可能会重新用于治疗 AD。