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最新研究揭示，透過抑制大腦星狀細胞中的IDO1酵素，可改善阿茲海默症患者海馬迴的葡萄糖代謝，恢復神經細胞的能量供應，進而提升記憶與認知功能。此發現為神經退化性疾病治療開啟全新契機。
Restoring hippocampal glucose metabolism rescues cognition across Alzheimer’s disease pathologies
恢復海馬迴的葡萄糖代謝可改善阿茲海默症病理下的認知功能
Minhas PS, Jones JR, Latif-Hernandez A, et al. Restoring hippocampal glucose metabolism rescues cognition across Alzheimer’s disease pathologies. Science. 2024;385(6711):eabm6131. doi:10.1126/science.abm6131
https://pubmed.ncbi.nlm.nih.gov/39172838/
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.
摘要
阿茲海默症（AD）的病理特徵之一是大腦葡萄糖代謝受損，近期蛋白質組學研究指出 AD 中神經膠質細胞代謝功能異常。本研究顯示，抑制將色胺酸代謝為犬尿喹啉酸（KYN）的吲哚胺-2,3-雙加氧酶1（IDO1），可透過恢復星狀膠質細胞代謝，改善小鼠 AD 臨床前模型的海馬迴記憶功能。β 類澱粉蛋白與 tau 寡聚體會透過芳香碳氫化合物受體（AhR）途徑激活星狀膠質細胞 IDO1，導致 KYN 增加並抑制糖解作用。在類澱粉蛋白和 tau 模型中，IDO1 抑制可透過單羧酸轉運蛋白依賴性機制，改善海馬迴葡萄糖代謝並恢復海馬迴長期增強作用（LTP）。在來自 AD 患者的星狀膠質細胞與神經元共培養系統中，IDO1 抑制可改善星狀膠質細胞的乳酸生成及神經元的乳酸攝取。因此，當前為癌症開發的 IDO1 抑制劑可能可重新應用於 AD 的治療。
編者摘要
阿茲海默症與大腦代謝異常密切相關。Minhas 等人透過人類誘導多能幹細胞與小鼠模型的結合研究了葡萄糖代謝受損在疾病進展中的作用（詳見 Johnson 與 Macauley 的專文述評）。作者發現，兩種阿茲海默症主要病理蛋白——類澱粉蛋白 β 和 tau 寡聚體——會激活吲哚胺-2,3-雙加氧酶 1（IDO1），促使色胺酸轉化為犬尿喹啉酸，進而抑制星狀膠質細胞的糖解作用，減少神經元的主要能量來源。在體外抑制 IDO1 可恢復突觸可塑性，在多種齧齒動物模型中也改善了認知功能。針對代謝功能障礙的治療策略為神經退化性疾病的治療帶來了希望。——Mattia Maroso
結構化摘要
引言
阿茲海默症（AD）是一種與年齡相關的神經退化性疾病，其特徵是突觸和神經迴路的逐漸且不可逆損失。影響突觸損失的主要病理生理過程，包括蛋白穩定性破壞、錯誤折疊的類澱粉蛋白和 tau 蛋白積累，以及小膠質細胞功能障礙，目前正被積極研究，以期找到能改變疾病進程的治療方法。然而，伴隨這些病理變化的，是持續性的腦部葡萄糖代謝下降。最新的蛋白質體學研究顯示，AD 患者的星狀膠質細胞和小膠質細胞代謝出現顯著異常。
研究理論
星狀膠質細胞產生乳酸，並將其輸送至神經元，為粒線體呼吸提供能量，支持突觸活動。近期研究顯示，吲哚胺-2,3-雙加氧酶1（IDO1）在多種神經退化性疾病中扮演重要角色，包括 AD。IDO1 是將色胺酸（TRP）轉化為犬尿喹啉酸（KYN）的限速酶，KYN 可透過與芳香碳氫化合物受體（AhR）相互作用，在發炎及腫瘤環境中引發免疫抑制。IDO1 活性會受到多種免疫原性刺激的顯著上調，在大腦中，IDO1 主要表現在星狀膠質細胞和小膠質細胞中，而非神經元，且其表現量可因發炎刺激而增加。
結果
本研究發現，抑制 IDO1 和 KYN 的產生，透過恢復星狀膠質細胞對神經元的代謝支持，在類澱粉蛋白和 tau 蛋白病理的臨床前模型中，改善了海馬迴的突觸可塑性和記憶功能。類澱粉蛋白 β 和 tau 寡聚體這兩種 AD 的主要病理效應分子，會透過 AhR 依賴性機制激活星狀膠質細胞中的 IDO1，增加 KYN 水平並抑制糖解作用。相反地，藥理性抑制 IDO1 可恢復星狀膠質細胞的糖解作用和乳酸生成。在產生類澱粉蛋白的 APPSwe-PS1∆E9 和 5XFAD 小鼠，以及產生 tau 蛋白的 P301S 小鼠中，IDO1 抑制可透過代謝組學和基質輔助雷射脫附游離質譜（MALDI-MS）分析，顯示海馬迴的葡萄糖代謝得到改善，並恢復空間記憶。此外，IDO1 抑制還可透過單羧酸轉運蛋白依賴性機制，恢復海馬迴長期增強作用（LTP），顯示 IDO1 活性會破壞星狀膠質細胞對神經元的代謝支持。質譜標記的人類星狀膠質細胞體外實驗證明，IDO1 調控星狀膠質細胞的乳酸生成，並促進神經元對乳酸的攝取。在來自 AD 患者的星狀膠質細胞與神經元共培養系統中，IDO1 抑制可修正星狀膠質細胞乳酸生成及向神經元的轉運缺陷，從而改善神經元的葡萄糖代謝。
結論
本研究揭示了 IDO1 在大腦葡萄糖代謝中的新作用，並強調了已用於輔助癌症治療的可穿透大腦的 IDO1 抑制劑，有潛力被重新應用於治療阿茲海默症等神經退化性疾病。本研究同時揭示了一種跨越多種病理的神經元功能障礙普遍機制。除了 AD 之外，IDO1 的調控可能對帕金森氏症痴呆症（其特徵是 α-突觸核蛋白與類澱粉蛋白的積累）以及廣泛的 tau 蛋白病變具有潛在應用。此外，KYN 代謝途徑相關代謝物的增加，也可能存在於其他與錯誤折疊蛋白積累相關的神經退化性疾病中，顯示星狀膠質細胞葡萄糖代謝缺陷可能是這些疾病的共同特徵。
星狀膠質細胞 IDO1 活性在阿茲海默症病理中的作用機制
（左圖）
星狀膠質細胞（綠色）透過糖解作用產生乳酸，糖解相關基因的表現部分由缺氧誘導因子 1-α（HIF1α）調控。足夠的乳酸從星狀膠質細胞轉移至神經元（藍色），以支持神經元粒線體的呼吸作用和突觸活動。
（中圖）
星狀膠質細胞中 IDO1 活性增加，產生更多犬尿喹啉酸（KYN），打破芳香碳氫化合物受體（AhR）與 HIF1α 核內訊號傳導之間的平衡，導致星狀膠質細胞的糖解作用減少，乳酸生成下降，對神經元的代謝支持減弱。
（右圖）
星狀膠質細胞 KYN 水平下降可恢復糖解作用，增強對神經元的代謝支持，並減輕類澱粉蛋白與 tau 蛋白病理的嚴重程度。
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