小柯机器人

韩国大田基础科学研究所 (IBS) C. Justin Lee和韩国科学技术研究院Hoon Ryu研究组取得一项新突破。他们发现星形细胞尿素循环解毒β-淀粉样蛋白 (Aβ)衍生氨会损害阿尔茨海默病（AD）患者的记忆。相关论文发表在2022年6月22日出版的《细胞-代谢》杂志上。

研究人员发现正常星形胶质细胞具有非循环尿素代谢，然而Aβ处理的星形胶质细胞则会发生尿素循环，其酶表达上调和起始代谢物天冬氨酸、起始底物氨、终产物尿素和副产物腐胺累积。基因沉默星形细胞鸟氨酸脱羧酶-1(ODC1)，促进鸟氨酸到腐胺的转化，促进尿素循环并消除异常腐胺及其有毒副产物氨、H2O2及其最终产物GABA，以恢复AD患者反应性星形胶质细胞增生和记忆障碍。

该研究结果表明星形细胞尿素循环在AD中发挥有益Aβ解毒和有害记忆障碍的相反作用。研究人员建议将抑制ODC1作为一种潜在的AD治疗策略，以促进有毒分子的去除和防止记忆丧失。

据介绍，阿尔茨海默病是最常见的神经退行性疾病之一，其特征是Aβ斑块和明显的进展性记忆丧失。在AD中，希望利用星形胶质细胞吸收和清除Aβ斑块。然而，Aβ诱导AD发生和记忆障碍的机制仍有待阐明。

附：英文原文

Title: Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimer’s disease

Author: Yeon Ha Ju, Mridula Bhalla, Seung Jae Hyeon, Ju Eun Oh, Seonguk Yoo, Uikyu Chae, Jea Kwon, Wuhyun Koh, Jiwoon Lim, Yongmin Mason Park, Junghee Lee, Il-Joo Cho, Hyunbeom Lee, Hoon Ryu, C. Justin Lee

Issue&Volume: 2022-06-22

Abstract: Alzheimer’s disease (AD) is one of the foremost neurodegenerative diseases, characterizedby beta-amyloid (Aβ) plaques and significant progressive memory loss. In AD, astrocytesare proposed to take up and clear Aβ plaques. However, how Aβ induces pathogenesisand memory impairment in AD remains elusive. We report that normal astrocytes shownon-cyclic urea metabolism, whereas Aβ-treated astrocytes show switched-on urea cyclewith upregulated enzymes and accumulated entering-metabolite aspartate, starting-substrateammonia, end-product urea, and side-product putrescine. Gene silencing of astrocyticornithine decarboxylase-1 (ODC1), facilitating ornithine-to-putrescine conversion,boosts urea cycle and eliminates aberrant putrescine and its toxic byproducts ammoniaand H2O2 and its end product GABA to recover from reactive astrogliosis and memory impairmentin AD. Our findings implicate that astrocytic urea cycle exerts opposing roles ofbeneficial Aβ detoxification and detrimental memory impairment in AD. We propose ODC1inhibition as a promising therapeutic strategy for AD to facilitate removal of toxicmolecules and prevent memory loss.

DOI: 10.1016/j.cmet.2022.05.011

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00193-0

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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