Enhanced Activities of Blood Thiamine Diphosphatase and Monophosphatase in Alzheimer's Disease

Pan, Xiaoli; Sang, Shaoming; Fei, Guoqiang; Jin, Lirong; Liu, Huimin; Wang, Zhiliang; Wang, Hui; Zhong, Chunjiu

doi:10.1371/journal.pone.0167273

Cited by 17 publications

(12 citation statements)

References 29 publications

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“…Therefore, having demonstrated that the cKO mice displayed neuronal loss and brain atrophy, as well as many other pathophysiological features of AD, our study strongly supports that TPK deficiency and the consequent impairment in thiamine metabolism in the brain constitute a pathogenic factor that underlies multiple pathophysiological features of AD and plays a critical role in disease pathogenesis. Ours and another previous study have shown that TPK activity was not significantly changed in brain and blood samples of AD patients compared to control subjects 18,19 . It is possible that the existing method of TPK activity measurement was insensitive due to the condition of optimal pH and Mg2+ concentration, as well as abundant substrates (ATP and thiamine).…”

Section: Discussionsupporting

confidence: 43%

Thiamine pyrophosphokinase deficiency induces Alzheimer’s pathology

Sang

Qian

Cai

et al. 2020

Preprint

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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.

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Section: Discussionsupporting

confidence: 43%

Thiamine pyrophosphokinase deficiency induces Alzheimer’s pathology

Sang

Qian

Cai

et al. 2020

Preprint

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“…Fourth, is brain glucose hypometabolism due to TDP reduction associated with other pathophysiological features of AD, such as tau hyperphosphorylation, neuroinflammation, insulin resistance, and microvascular dysfunction? Finally, our previous study showed that enhanced activities of phosphatases contribute to TDP reduction in AD [ 41 ]. What is the mechanism?…”

Section: Discussionmentioning

confidence: 99%

Thiamine diphosphate reduction strongly correlates with brain glucose hypometabolism in Alzheimer’s disease, whereas amyloid deposition does not

et al. 2018

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BackgroundThe underlying mechanism of brain glucose hypometabolism, an invariant neurodegenerative feature that tightly correlates with cognitive impairment and disease progression of Alzheimer’s disease (AD), remains elusive.MethodsPositron emission tomography with 2-[18F]fluoro-2-deoxy-d-glucose (FDG-PET) was used to evaluate brain glucose metabolism, presented as the rate of 2-[18F]fluoro-2-deoxy-d-glucose standardized uptake value ratio (FDG SUVR) in patients with AD or control subjects and in mice with or without thiamine deficiency induced by a thiamine-deprived diet. Brain amyloid-β (Aβ) deposition in patients with clinically diagnosed AD was quantified by performing assays using 11C-Pittsburgh compound B PET. The levels of thiamine metabolites in blood samples of patients with AD and control subjects, as well as in blood and brain samples of mice, were detected by high-performance liquid chromatography with fluorescence detection.ResultsFDG SUVRs in frontal, temporal, and parietal cortices of patients with AD were closely correlated with the levels of blood thiamine diphosphate (TDP) and cognitive abilities, but not with brain Aβ deposition. Mice on a thiamine-deprived diet manifested a significant decline of FDG SUVRs in multiple brain regions as compared with those in control mice, with magnitudes highly correlating with both brain and blood TDP levels. There were no significant differences in the changes of FDG SUVRs in observed brain regions between amyloid precursor protein/presenilin-1 and wild-type mice following thiamine deficiency.ConclusionsWe demonstrate, for the first time to our knowledge, in vivo that TDP reduction strongly correlates with brain glucose hypometabolism, whereas amyloid deposition does not. Our study provides new insight into the pathogenesis and therapeutic strategy for AD.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0354-2) contains supplementary material, which is available to authorized users.

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“…Furthermore, a recent case-control study of humans showed that blood thiamine diphosphate concentration was significantly reduced in patients with AD relative to controls and had an AUROC of 77.4%, sensitivity of 78.1%, and specificity of 77.2% (125). A subsequent study reported that thiamine phophatases are increased in the blood of patients with AD, which may explain the low thiamine diphosphate concentration in AD (126).…”

Section: Current Status Of Knowledgementioning

confidence: 97%

Vitamins Associated with Brain Aging, Mild Cognitive Impairment, and Alzheimer Disease: Biomarkers, Epidemiological and Experimental Evidence, Plausible Mechanisms, and Knowledge Gaps

Fenech

2017

Advances in Nutrition

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The key to preventing brain aging, mild cognitive impairment (MCI), and Alzheimer disease (AD) via vitamin intake is first to understand molecular mechanisms, then to deduce relevant biomarkers, and subsequently to test the level of evidence for the impact of vitamins in the relevant pathways and their modulation of dementia risk. This narrative review infers information on mechanisms from gene and metabolic defects associated with MCI and AD, and assesses the role of vitamins using recent results from animal and human studies. Current evidence suggests that all known vitamins and some "quasi-vitamins" are involved as cofactors or influence ≥1 of the 6 key sets of pathways or pathologies associated with MCI or AD, relating to ) 1-carbon metabolism,) DNA damage and repair, ) mitochondrial function and glucose metabolism,) lipid and phospholipid metabolism and myelination, ) neurotransmitter synthesis and synaptogenesis, and) amyloidosis and Tau protein phosphorylation. The contemporary level of evidence for each of the vitamins varies considerably, but it is notable that B vitamins are involved as cofactors in all of the core pathways or pathologies and, together with vitamins C and E, are consistently associated with a protective role against dementia. Outcomes from recent studies indicate that the efficacy and safety of supplementation with vitamins to prevent MCI and the early stages of AD will most likely depend on ) which pathways are defective,) which vitamins are deficient and could correct the relevant metabolic defects, and ) the modulating impact of nutrient-nutrient and nutrient-genotype interaction. More focus on a precision nutrition approach is required to realize the full potential of vitamin therapy in preventing dementia and to avoid causing harm.

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Enhanced Activities of Blood Thiamine Diphosphatase and Monophosphatase in Alzheimer's Disease

Cited by 17 publications

References 29 publications

Thiamine pyrophosphokinase deficiency induces Alzheimer’s pathology

Thiamine pyrophosphokinase deficiency induces Alzheimer’s pathology

Thiamine diphosphate reduction strongly correlates with brain glucose hypometabolism in Alzheimer’s disease, whereas amyloid deposition does not

Vitamins Associated with Brain Aging, Mild Cognitive Impairment, and Alzheimer Disease: Biomarkers, Epidemiological and Experimental Evidence, Plausible Mechanisms, and Knowledge Gaps

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