Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies

Affiliations

• 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.
• Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
• Central Institute for Experimental Medicine and Life Science, Keio University, 3-25-12 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.
• WPI-Bio2Q Research Center, Keio University, 3-25-12 Tonomachi, Kawasaki-ku, Kawasaki 210-0821 Japan.
• Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
• Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
• Lewis Institute for Cancer Research, Princeton University, Princeton, NJ 08544, USA.
• Department of Chemistry, Princeton University, Princeton 08544 NJ, USA.
• Department of Biochemistry and Molecular Biology, Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
• Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94143, USA.
• Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ 85351, USA.
• Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
• Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
• The Phil and Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, CA 94305, USA.

PMID: 39172838 DOI: 10.1126/science.abm6131

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.

大脑葡萄糖代谢障碍是阿尔茨海默病（AD）的一个病理特征，最近的蛋白质组学研究突显了AD中神经胶质细胞代谢的紊乱。我们报告了通过抑制吲哚胺-2,3-双加氧酶1（IDO1），该酶将色氨酸代谢为犬尿氨酸（KYN），能够通过恢复星形胶质细胞代谢来拯救小鼠临床前模型中的海马记忆功能。淀粉样蛋白β和tau寡聚体激活星形胶质细胞中的IDO1，增加KYN的生成，并以芳香烃受体（AhR）依赖的方式抑制糖酵解。在淀粉样蛋白和tau模型中，抑制IDO1改善了海马体的葡萄糖代谢，并以单羧酸转运蛋白依赖的方式恢复了海马体的长期增强效应。在来自AD患者的星形胶质细胞和神经元共培养体系中，抑制IDO1改善了星形胶质细胞乳酸的生成及其被神经元的摄取。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。

INTRODUCTION

阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，其特征是突触和神经回路的逐渐且不可逆的丧失。导致突触丧失的主要病理生理过程，正在被积极研究，包括蛋白质稳态失调、误折叠的淀粉样蛋白和tau蛋白的积累以及小胶质细胞功能障碍，旨在寻找新的治疗方法。然而，与这些独特的病理状态同时存在的是大脑葡萄糖代谢的持续下降，最近的蛋白质组学研究揭示了AD患者星形胶质细胞和小胶质细胞代谢的显著紊乱。

RATIONALE

星形胶质细胞生成乳酸，这些乳酸被转运到神经元中以供给线粒体呼吸并支持突触活动。最近的研究表明，吲哚胺-2,3-双加氧酶1（IDO1），一种在星形胶质细胞中表达的酶，在多种神经退行性疾病中，包括阿尔茨海默病（AD），发挥着作用。IDO1是将色氨酸（TRP）转化为犬尿氨酸（KYN）的限速酶，KYN是一种通过与芳香烃受体（AhR）相互作用在炎症和肿瘤环境中引发免疫抑制的代谢物。IDO1的活性在各种免疫原性刺激下显著上调，在大脑中，IDO1在星形胶质细胞和小胶质细胞中表达，但在神经元中不表达，尽管其水平可以在炎症刺激下增加。

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