Exposure to pyrithiamine increases β-amyloid accumulation, Tau hyperphosphorylation, and glycogen synthase kinase-3 activity in the brain.

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.