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Impairment of Thiamine Transport at the GUT-BBB-AXIS Contributes to Wernicke’s Encephalopathy

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Abstract

Wernicke’s encephalopathy, a common neurological disease, is caused by thiamine (vitamin B1) deficiency. Neuropathy resulting from thiamine deficiency is a hallmark of Wernicke-Korsakoff syndrome in chronic alcohol users. The underlying mechanisms of this deficiency and progression of neuropathy remain to be understood. To uncover the unknown mechanisms of thiamine deficiency in alcohol abuse, we used chronic alcohol consumption or thiamine deficiency diet ingestion in animal models. Observations from animal models were validated in primary human neuronal culture for neurodegenerative process. We employed radio-labeled bio-distribution of thiamine, qualitative and quantitative analyses of the various biomarkers and neurodegenerative process. In the present studies, we established that disruption of thiamine transport across the intestinal gut blood-brain barrier axis as the cause of thiamine deficiency in the brain for neurodegeneration. We found that reduction in thiamine transport across these interfaces was the cause of reduction in the synthesis of thiamine pyrophosphate (TPP), an active cofactor for pyruvate dehydrogenase E1α (PDHE1α). Our findings revealed that decrease in the levels of PDHE1α cofactors switched on the activation of PD kinase (PDK) in the brain, thereby triggering the neuronal phosphorylation of PDHE1α (p-PDHE1α). Dysfunctional phosphorylated PDHE1α causes the reduction of mitochondrial aerobic respiration that led to neurodegeneration. We concluded that impairment of thiamine transport across the gut-BBB-axis that led to insufficient TPP synthesis was critical to Wernicke-neuropathy, which could be effectively prevented by stabilizing the thiamine transporters.

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Acknowledgements

The National Institute of Health (NIH/NIAAA) supported the work.

Funding

This work was supported by NIH/NIAAA grant 1R21AA022734-01A1, R21 AA020370-01A1 (to JH).

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Authors and Affiliations

  1. Laboratory of Neurovascular Inflammation and Neurodegeneration, Department of Biomedical Engineering, Center for Injury Bio Mechanics, Materials and Medicine, New Jersey Institute of Technology, 111 Lock Street, Newark, NJ, 07102, USA

    P. M. Abdul-Muneer, Xiaotang Ma & James Haorah

  2. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Saleena Alikunju, Heather Schuetz & Adam M. Szlachetka

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  1. P. M. Abdul-Muneer
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Contributions

PMAM carried out the studies, performed the acquisition data and involved in manuscript preparation. HS and SA assisted PMAM in experiments and data acquisition. AMS performed the animal care, and pair-feeding, XM helped JH with the manuscript preparation and figure design. JH designed the whole project, supervised the experiments, data interpretation and prepared the manuscript. All authors read and approved the final manuscript.

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Correspondence to James Haorah.

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Elective abortus specimens of human fetal brain tissues were obtained in full compliance with the ethical guidelines of the National Institutes of Health and University of Nebraska Medical Center. No disclosure of the source of abortus tissue or of patient information was possible since only de-identified abortus tissues were obtained from the source. In all instances, informed consent was obtained and maintained by the source.

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Abdul-Muneer, P.M., Alikunju, S., Schuetz, H. et al. Impairment of Thiamine Transport at the GUT-BBB-AXIS Contributes to Wernicke’s Encephalopathy. Mol Neurobiol 55, 5937–5950 (2018). https://doi.org/10.1007/s12035-017-0811-0

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  • DOI: https://doi.org/10.1007/s12035-017-0811-0

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