Thiamine pyrophosphokinase deficiency induces Alzheimer’s pathology

Background Thiamine diphosphate (TDP) reduction plays an important role in cerebral glucose hypometabolism, the neurodegenerative indicator, in Alzheimer’s disease (AD). The mechanism underlying TDP reduction remains elusive. Thus, it is critical to define the mechanism and its effect on neurodegeneration, the pathological basis of the disease occurrence and progression. Methods The mRNA levels of all known genes associated with thiamine metabolism, including thiamine pyrophosphokinase ( TPK ), Solute Carrier Family 19 Member 2 (SLC19A2) , SLC19A3 , and SLC25A19 , in brain samples of patients with AD and other neurodegenerative disorders in multiple independent datasets were analyzed. TPK protein levels were further examined in the brain tissues of AD patients and control subjects. A mouse model with conditional knockout (cKO) of TPK gene in the excitatory neurons of adult brain was established. Results The brain TPK mRNA level was markedly lower in AD patients, but not in other neurodegenerative disorders. The brain TPK protein level was also significantly decreased in AD patients. TPK gene knockout in the mice caused cerebral glucose hypometabolism, β-amyloid deposition, Tau hyperphosphorylation, neuroinflammation, and neuronal loss and brain atrophy. Cross-species correlation analysis revealed the similar changes of gene profiling between the cKO mice and AD patients. Conclusions The deficiency of brain TPK, a key enzyme for TDP synthesis, is specific to AD. The cKO mice show AD-associated phenotypes and could serve as a new mouse model for AD studies. Our study provides a novel insight into the critical role of TPK in AD pathogenesis and its potential for the disease treatment. ### Competing Interest Statement Chunjiu Zhong, the corresponding author, holds shares of Shanghai Rixin Bitech Co., Ltd., which is dedicated to developing drugs for the prevention and treatment of AD. The other authors declare that they have no competing interests.