期刊
NEUROBIOLOGY OF AGING
卷 32, 期 1, 页码 42-53出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2009.01.005
关键词
beta-Amyloid peptide; beta-Secretase; Thiamine deficiency; Oxidative stress; Alzheimer's disease
资金
- Ministry of Science and Technology of China [2007CB947100]
- National Natural Science Foundation of China [30870812, 30570580, 30471452, 30470544]
- Chinese Academy of Sciences [KSCX2-YW-R-115, SIBS2008006]
- Shanghai Institutes for Biological Sciences
- Science and Technology Commission of Shanghai Municipality [07DJ14005]
- Shanghai Municipality
- NIH/NIAAA [AA015407]
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [R01AA015407] Funding Source: NIH RePORTER
Thiamine pyrophosphate (TPP) and the activities of thiamine-dependent enzymes are reduced in Alzheimer's disease (AD) patients. In this study, we analyzed the relationship between thiamine deficiency (TD) and amyloid precursor protein (APP) processing in both cellular and animal models of TD. In SH-SY5Y neuroblastoma cells overexpressing APP, TD promoted maturation of beta-site APP cleaving enzyme 1 (BACE I) and increased P-secretase activity which resulted in elevated levels of beta-amyloid (A beta) as well as beta-secretase cleaved C-terminal fragment (beta-CTF). An inhibitor of P-secretase efficiently reduced TD-induced up-regulation of A beta and beta-CTF. Importantly, thiamine supplementation reversed the TD-induced alterations. Furthermore, TD treatment caused a significant accumulation of reactive oxygen species (ROS); antioxidants suppressed ROS production and maturation of BACE1, as well as TD-induced A beta accumulation. On the other hand, exogenous A beta(1-40) enhanced TD-induced production of ROS. A study on mice indicated that TD also caused A beta accumulation in the brain, which was reversed by thiamine supplementation. Taken together, our study suggests that TD could enhance A beta generation by promoting p-secretase activity, and the accumulation of A beta subsequently exacerbated TD-induced oxidative stress. (C) 2009 Elsevier Inc. All rights reserved.
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