Thiamine pyrophosphokinase-1 deficiency in neurons drives Alzheimer's multiple pathophysiological alterations

BackgroundThe mechanism driving multiple pathophysiological alterations in Alzheimers disease (AD) remains unclear. Thiamine deficiency, a well-known feature of AD, may contribute to these alterations. MethodsThe expressions of four known genes associated with thiamine metabolism were studied in brain samples from patients with AD and other neurodegenerative disorders. The results were further demonstrated in AD and diabetic mouse and cellular models. The phenotypes of mice with conditional Thiamine pyrophosphokinase-1 (Tpk) knockout in brain excitatory neurons were investigated. The therapeutic effects of thiamine diphosphate supplement and Tpk delivery on cellular and mouse models were explored. Phase 2 clinical trial of benfotiamine, a thiamine derivative, plus donepezil was performed. ResultsOnly TPK expression was inhibited in brain samples of AD patients, while none of thiamine-associated genes were significantly changed in other neurodegenerative disorders. TPK inhibition in the brains and neurons was verified in AD and diabetic mouse and cellular models. Mice with Tpk deletion in neurons exhibited all major pathophysiological alterations of AD, including amyloid deposition, Tau hyperphosphorylation, and brain atrophy. TPK expression restoration and thiamine diphosphate supplement ameliorated the pathophysiological and behavioral phenotypes in mouse and cell models with Tpk insufficiency. Benfotiamine delayed cognitive decline in mild-to-moderate AD patients with a dose-effect relationship, particularly with a significant attenuation of the deterioration in moderate AD patients by post hoc analysis. ConclusionsTPK deficiency and hence thiamine diphosphate reduction in neurons are a decisive factor driving multiple pathophysiologic alterations of AD, unveiling a new direction for the disease mechanism and treatment.