title: Thiamine deficiency increases β-secretase activity and accumulation of β-amyloid peptides.
abstract: 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 β-site APP cleaving enzyme 1 (BACE1) and increased β-secretase activity which resulted in elevated levels of β-amyloid (Aβ) as well as β-secretase cleaved C-terminal fragment (β-CTF). An inhibitor of β-secretase efficiently reduced TD-induced up-regulation of Aβ and β-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 Aβ accumulation. On the other hand, exogenous Aβ(1-40) enhanced TD-induced production of ROS. A study on mice indicated that TD also caused Aβ accumulation in the brain, which was reversed by thiamine supplementation. Taken together, our study suggests that TD could enhance Aβ generation by promoting β-secretase activity, and the accumulation of Aβ subsequently exacerbated TD-induced oxidative stress.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, PR China.
authors.forename: Qipeng
authors.initials: Q
authors.lastname: Zhang
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Wenxia
authors.initials: W
authors.lastname: Li
authors.forename: Zhiqin
authors.initials: Z
authors.lastname: Fan
authors.forename: Anyang
authors.initials: A
authors.lastname: Sun
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.forename: Zun-Ji
authors.initials: ZJ
authors.lastname: Ke
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D002839:Chromans / Q000627:therapeutic use; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D011745:Pyrithiamine / Q000009:adverse effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013831:Thiamine / Q000008:administration & dosage; D013832:Thiamine Deficiency / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D002839:Chromans; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); D011745:Pyrithiamine; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D013831:Thiamine