Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA.
Science. 2024 Aug 23;385(6711):eabm6131. doi: 10.1126/science.abm6131.
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.
脑葡萄糖代谢受损是阿尔茨海默病（AD）的病理特征，最近的蛋白质组学研究强调了 AD 中神经胶质代谢的紊乱。我们报告称，色氨酸 2,3-双加氧酶 1（IDO1）的抑制可通过恢复星形胶质细胞代谢来挽救 AD 临床前模型中的海马记忆功能，IDO1 可将色氨酸代谢为犬尿氨酸（KYN）。淀粉样蛋白β和 tau 寡聚体激活星形胶质细胞 IDO1 会以芳烃受体依赖性的方式增加 KYN 并抑制糖酵解。在淀粉样蛋白和 tau 模型中，IDO1 抑制通过单羧酸转运蛋白依赖性方式改善海马葡萄糖代谢并挽救海马长时程增强。在 AD 患者的星形胶质细胞和神经元共培养物中，IDO1 抑制可改善星形胶质细胞产生的乳酸和神经元摄取。因此，目前为癌症开发的 IDO1 抑制剂可能被重新用于 AD 的治疗。
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