Exposure to Pyrithiamine Increases β-Amyloid Accumulation, Tau Hyperphosphorylation, and Glycogen Synthase Kinase-3 Activity in the Brain

Abstract

Decreased thiamine-dependent enzyme activity and/or thiamine deficiency (TD) have been linked to Alzheimer's disease (AD). In this study, we administered pyrithiamine, an anti-thiamine compound, to both APP/PS1 transgenic mice and wild-type littermate control mice; alternatively, we induced TD by thiamine-depleted diet. Pyrithiamine treatment and diet-induced TD impaired the memory of wild-type mice, but had little effect on APP/PS1 mice. Pathophysiologically, pyrithiamine treatment and diet-induced TD aggravated β-amyloid accumulation in the brain. This was demonstrated by increased β-amyloid in the brains of wild-type mice using ELISA and by the number of amyloid plaques in the brains of APP/PS1 transgenic mice using immunochemical staining. Also, enhanced numbers of phosphorylated Tau-positive cells were observed in both APP/PS1 transgenic and wild-type mice. Furthermore, pyrithiamine decreased the phosphorylation rates of glycogen synthase kinase (GSK)-3β and raised its enzymatic activity, but had little influence on GSK-3α. Diet-induced TD reduced the phosphorylated rates and increased the activities of GSK-3, GSK-3α, and GSK-3β. These results suggest that when sufficient thiamine supplement is administered, pyrithiamine can cause AD-like pathological alterations similar to that of diet-induced TD.

Thiamine metabolism is critical for regulating correlated growth of dendrite arbors and neuronal somata

“…We further tested these effects using a complementary pharmacological approach, by treating neurons with pyrithiamine, a competitive substrate for Tpk1 that can be phosphorylated to form pyrithiamine diphosphate 18 but cannot functionally substitute for TDP. Pyrithiamine treatment has been shown to induce symptoms similar to those of thiamine deficiency in animals 19 . Neurons were transfected with GFP on DIV 6, and treated with pyrithiamine (50 μM) from DIV 7 to DIV 9.…”

Involvement of Insulin Signaling Disturbances in Bisphenol A-Induced Alzheimer’s Disease-like Neurotoxicity

“…As we speculated, BPA exposure significantly decreased the phosphorylation of mTOR and methylation level of PP2A, suggesting the adverse effects of BPA on insulin signaling pathway. The increases in the activities of GSK-3α and β are responsible for APP generation and the hyper-phosphorylation of tau, respectively 37 ; thus, these findings prompted us to infer that BPA exposure results in the enhancement of APP and p-tau expression. As speculated, the APP and p-tau expressions were substantially elevated after BPA exposure in SY5Y cells, and these effects were confirmed in another cell line, PC-12, which suggests that BPA affects APP and p-tau generation.…”

Long-Term Cognitive Improvement After Benfotiamine Administration in Patients with Alzheimer’s Disease

“…Our previous study showed that TDP reduction is a significant biomarker for AD diagnosis [10]. The reduction of brain glucose metabolism and its possible pathogenic indicator, TDP reduction, implicate multiple pathogenic pathways in AD, including oxidative stress [11], neuroinflammation [12], and enhanced activity of glycogen synthase kinase-3 [13] and b-secretase [14]. Therefore, we hypothesized that disruption of thiamine metabolism directly contributes to AD pathogenesis by perturbing glucose utilization and by activating multiple pathophysiological cascades in the brain [15].…”