文摘
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 x3b2;-site APP cleaving enzyme 1 (BACE1) and increased x3b2;-secretase activity which resulted in elevated levels of x3b2;-amyloid (Ax3b2;) as well as x3b2;-secretase cleaved C-terminal fragment (x3b2;-CTF). An inhibitor of x3b2;-secretase efficiently reduced TD-induced up-regulation of Ax3b2; and x3b2;-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 Ax3b2; accumulation. On the other hand, exogenous Ax3b2;1–40 enhanced TD-induced production of ROS. A study on mice indicated that TD also caused Ax3b2; accumulation in the brain, which was reversed by thiamine supplementation. Taken together, our study suggests that TD could enhance Ax3b2; generation by promoting x3b2;-secretase activity, and the accumulation of Ax3b2; subsequently exacerbated TD-induced oxidative stress.