Thiamine deficiency increases beta-secretase activity and accumulation of beta-amyloid peptides.
Neurobiol Aging. 2009 Feb 20;
Authors: Zhang Q, Yang G, Li W, Fan Z, Sun A, Luo J, Ke ZJ
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 (BACE1) and increased beta-secretase activity which resulted in elevated levels of beta-amyloid (Abeta) as well as beta-secretase cleaved C-terminal fragment (beta-CTF). An inhibitor of beta-secretase efficiently reduced TD-induced up-regulation of Abeta 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 Abeta accumulation. On the other hand, exogenous Abeta(1-40) enhanced TD-induced production of ROS. A study on mice indicated that TD also caused Abeta accumulation in the brain, which was reversed by thiamine supplementation. Taken together, our study suggests that TD could enhance Abeta generation by promoting beta-secretase activity, and the accumulation of Abeta subsequently exacerbated TD-induced oxidative stress.
PMID: 19233513 [PubMed - as supplied by publisher]