期刊
NEUROTHERAPEUTICS
卷 15, 期 4, 页码 1036-1054出版社
SPRINGER
DOI: 10.1007/s13311-018-0669-5
关键词
Alzheimer's disease; L-norvaline; L-arginine; arginase; ribosomal protein S6 kinase beta-1; mTOR
资金
- Marie Curie CIG Grant [322113]
- Leir Foundation
- Ginzburg Family Foundation
- Katz Foundation
The urea cycle is strongly implicated in the pathogenesis of Alzheimer's disease (AD). Arginase-I (ARGI) accumulation at sites of amyloid-beta (A beta) deposition is associated with L-arginine deprivation and neurodegeneration. An interaction between the arginase II (ARGII) and mTOR-ribosomal protein S6 kinase beta-1 (S6K1) pathways promotes inflammation and oxidative stress. In this study, we treated triple-transgenic (3xTg) mice exhibiting increased S6K1 activity and wild-type (WT) mice with L-norvaline, which inhibits both arginase and S6K1. The acquisition of spatial memory was significantly improved in the treated 3xTg mice, and the improvement was associated with a substantial reduction in microgliosis. In these mice, increases in the density of dendritic spines and expression levels of neuroplasticity-related proteins were followed by a decline in the levels of A beta toxic oligomeric and fibrillar species in the hippocampus. The findings point to an association of local A beta-driven and immune-mediated responses with altered L-arginine metabolism, and they suggest that arginase and S6K1 inhibition by L-norvaline may delay the progression of AD.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据