Department of Pharmaceutical Sciences, School of Pharmacy, University of California-Irvine, USA; Institute for Genomics and Bioinformatics, School of Information and Computer Sciences, University of California-Irvine, USA; Center for the Neurobiology of Learning and Memory, University of California-Irvine, Irvine, USA.
Division of Basic and Clinical Immunology, Department of Medicine, University of California Irvine, Irvine, CA 92697, USA.
J Neuroimmunol. 2022 May 15;366:577843. doi: 10.1016/j.jneuroim.2022.577843. Epub 2022 Mar 10.
The disruption of methionine (L-MET) metabolism has been linked with neurodevelopmental disorders such as autism and schizophrenia and neurodegenerative disorders such as Alzheimer's disorder. We previously showed that repeated administration to adult mice of methionine produced impairments of cognitive deficits. Considering the decreased neurogenesis and increased molecular inflammation hypotheses of cognitive deficits in Alzheimer's, we aimed to explore whether the methionine regimen that produced cognitive deficits is associated with altered neuroinflammation, neurogenesis, or neurodegeneration. We found that repeated administration of L-MET at a dose equivalent to two-fold of daily dietary intake for seven days enhanced the activation of microglia and inflammation in the brain, and decreased neurogenesis in the hippocampus without affecting degeneration. Furthermore, sub-chronic and chronic L-MET treatment of human neuroblastoma (SH-SY5Y) inhibited cell cycle progression, an effect that was reversed by decreasing removing L-MET from the medium. These results support a role for neuroinflammation and neurogenesis in mediating the mechanism through which L-MET induces cognitive deficits. The results also uncover L-MET restriction, neuroinflammation, and neurogenesis as potential preventive and/or therapeutic targets for mental disorders associated with cognitive disorders, including schizophrenia and Alzheimer's disease.
蛋氨酸（L-MET）代谢的紊乱与神经发育障碍（如自闭症和精神分裂症）和神经退行性疾病（如阿尔茨海默病）有关。我们之前的研究表明，反复给成年小鼠施用蛋氨酸会导致认知缺陷。考虑到阿尔茨海默病中认知缺陷的神经发生减少和分子炎症增加的假说，我们旨在探索是否导致认知缺陷的蛋氨酸方案与改变的神经炎症、神经发生或神经退行性变有关。我们发现，重复给予相当于两倍日常饮食摄入量的 L-MET 剂量七天会增强大脑中小胶质细胞的激活和炎症，并且减少海马体中的神经发生，而不会影响退化。此外，亚慢性和慢性 L-MET 处理人神经母细胞瘤（SH-SY5Y）抑制细胞周期进程，而通过从培养基中去除 L-MET 可以逆转该效应。这些结果支持神经炎症和神经发生在介导 L-MET 诱导认知缺陷的机制中的作用。这些结果还揭示了 L-MET 限制、神经炎症和神经发生作为与认知障碍相关的精神障碍（包括精神分裂症和阿尔茨海默病）的潜在预防和/或治疗靶点。
