研究人员抑制色氨酸-2,3-双加氧酶1（IDO1），它将色氨酸代谢为犬尿喹啉酸（KYN），能够通过恢复星形胶质细胞代谢来拯救小鼠阿尔茨海默病（AD）临床前模型中的海马记忆功能。淀粉样β蛋白和tau寡聚体激活星形胶质细胞中的IDO1，增加KYN并通过芳香烃受体依赖性机制抑制糖酵解。
在淀粉样蛋白和tau模型中，IDO1抑制改善了海马葡萄糖代谢，并以单羧酸转运蛋白依赖性机制拯救了海马长时程增强。在来自AD患者的星形胶质细胞和神经元共培养中，IDO1抑制改善了星形胶质细胞的乳酸产生和神经元的摄取。因此，目前开发用于癌症的IDO1抑制剂可能会被重新用于AD的治疗。
据了解，受损的脑葡萄糖代谢是AD的病理特征，最近的蛋白质组学研究突出了AD中胶质细胞代谢的破坏。
附：英文原文
Title: Restoring hippocampal glucose metabolism rescues cognition across Alzheimer’s disease pathologies
Author: Paras S. Minhas, Jeffrey R. Jones, Amira Latif-Hernandez, Yuki Sugiura, Aarooran S. Durairaj, Qian Wang, Siddhita D. Mhatre, Takeshi Uenaka, Joshua Crapser, Travis Conley, Hannah Ennerfelt, Yoo Jin Jung, Ling Liu, Praveena Prasad, Brenita C. Jenkins, Yeonglong Albert Ay, Matthew Matrongolo, Ryan Goodman, Traci Newmeyer, Kelly Heard, Austin Kang, Edward N. Wilson, Tao Yang, Erik M. Ullian, Geidy E. Serrano, Thomas G. Beach, Marius Wernig, Joshua D. Rabinowitz, Makoto Suematsu, Frank M. Longo, Melanie R. McReynolds, Fred H. Gage, Katrin I. Andreasson
Issue&Volume: 2024-08-23
Abstract: 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.
DOI: abm6131
Source:https://www.science.org/doi/10.1126/science.abm6131