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

阿尔茨海默病 (AD) 是最重要的神经退行性疾病之一，其特征是 β-淀粉样蛋白 (Aβ) 斑块和显着的进行性记忆丧失。在 AD 中，建议星形胶质细胞吸收和清除 Aβ 斑块。然而，Aβ如何诱导AD的发病机制和记忆障碍仍然难以捉摸。我们报告正常星形胶质细胞显示非循环尿素代谢，而 Aβ 处理的星形胶质细胞显示开启的尿素循环，酶上调和积累的进入代谢物天冬氨酸、起始底物氨、终产物尿素和副产物腐胺。星形细胞鸟氨酸脱羧酶-1 (ODC1) 的基因沉默，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和 H ₂ O ₂及其最终产物 GABA 从 AD 中的反应性星形胶质细胞增生和记忆障碍中恢复。我们的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。我们建议将 ODC1 抑制作为一种有前途的 AD 治疗策略，以促进有毒分子的去除和防止记忆丧失。