Pathophysiology of vitamin B1 (thiamin) transport in Alzheimer's disease

阿尔茨海默病（Alzheimer's disease，AD）是一种以β-淀粉样蛋白（Aβ）为特征的神经退行性疾病。 包括斑块神经纤维缠结和认知缺陷线粒体功能障碍，氧化应激 和减少的葡萄糖代谢是AD的一致特征。AD的病理生理学还包括 神经炎症，其与促炎细胞因子的升高相关（例如，例如，在一个实施例中，肿瘤坏死因子-α、 白细胞介素1β）。 硫胺素（维生素B1;也被称为“能量维生素”）是正常氧化不可或缺的。 线粒体中的能量代谢和ATP的产生;它也在减少细胞内 氧化应激因此，缺乏硫胺素在细胞水平导致损伤的氧化能 代谢，细胞ATP水平降低，并倾向于氧化应激;它还导致 线粒体功能/结构受损。 令人信服的证据表明，维生素B1的稳态在AD中被改变，维生素B1的缺乏可能导致AD的发生。 维生素A代谢疾病的病理。脑细胞通过一个专门的载体介导的过程从血液中获得硫胺素，该过程涉及硫胺素转运蛋白-1和-2（SLC 19 A2和SLC 19 A3基因的产物， 分别）。一旦内化，硫胺素被酶促转化为焦磷酸硫胺素（TPP），然后 通过另一个专门的载体介导的过程， TPP转运蛋白（MTPPT; SLC 25 A19基因的产物）。我们实验室最近的初步研究 与母体R 01资助相关的研究表明，在两种不同的人类/动物组织（胰腺和 肠），长时间暴露于促炎细胞因子导致细胞硫胺素的显著抑制， 摄取以及TPP转运到线粒体中。根据这些数据，我们假设硫胺素 脑细胞的摄取和随后将TPP转运到其线粒体中同样受到慢性炎症的影响。 暴露于促炎细胞因子。这反过来又导致细胞硫胺素水平不足/次优， 氧化代谢/ATP产生的损伤、氧化应激的增加和 线粒体的功能/结构，这可能有助于AD的发病机制。我们将检验这一假设 通过实现以下具体目的：1）研究表达水平的可能变化， AD患者脑内不同区域的硫胺素转运体SLC 19 A2、SLC 19 A3和SLC 25 A19; 检查脑细胞暴露于促炎细胞因子对细胞硫胺素摄取的影响， 将TPP转运到其线粒体中并确定所涉及的分子机制; 3）确定 小鼠模型脑中THTR-1、THTR-2和MTPPT的表达和活性水平的变化 的AD。

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by Amyloid-β peptide (Aβ)- containing plaques, neurofibrillary tangles and cognitive deficits. Mitochondrial dysfunction, oxidative stress and diminished glucose metabolism are consistent features of AD. The pathophysiology of AD also includes neuroinflammation, which is associated with an elevation of pro-inflammatory cytokines (e. g., TNF-α, interleukin 1β). Thiamine (vitamin B1; also referred to as the “energy vitamin”) is indispensable for normal oxidative energy metabolism and ATP production in the mitochondria; it also plays an important role in reducing cellular oxidative stress. Thus, deficiency of thiamine at the cellular level leads to impairment in oxidative energy metabolism, a decrease in cellular ATP level, and to a propensity for oxidative stress; it also leads to impairment in the function/structure of mitochondria. Compelling evidence exists suggesting that thiamine homeostasis is altered in AD, and that deficiency of the vitamin aggravates disease pathology. Brain cells obtain thiamin from the blood via a specialized carriermediated process that involves thiamine transporter-1 and -2 (products of the SLC19A2 and SLC19A3 genes, respectively). Once internalized, thiamine is enzymatically converted to thiamin pyrophosphate (TPP) then transported into mitochondria via another specialized carrier-mediated process that involves the mitochondrial TPP transporter (MTPPT; product of the SLC25A19 gene). Recent preliminary studies from our laboratory related to the parent R01 grant have shown that in two different human/animal tissues (the pancreas and the intestine), prolonged exposure to pro-inflammatory cytokines leads to a significant inhibition in cellular thiamin uptake as well as in transport of TPP into mitochondria. Given these data, we hypothesize here that thiamine uptake by brain cells and subsequent transport of TPP into their mitochondria is similarly impacted by chronic exposure to proinflammatory cytokines. This in turn leads to deficient/suboptimal cellular thiamine levels and impairment in oxidative metabolism/ATP production, an increase in oxidative stress, and abnormality in function/structure of mitochondria, which may contribute to the pathogenesis of AD. We will test this hypothesis by accomplishing the following Specific Aims: 1) Investigate possible changes in level of expression of the thiamine transporters SLC19A2, SLC19A3 and SLC25A19 in different regions of the brains of AD patients; 2) Examine the effect of exposure of brain cells to pro-inflammatory cytokines on cellular thiamine uptake and transport of TPP into their mitochondria and determine the molecular mechanisms involved; 3) Determine changes in the level of expression and activity of THTR-1, THTR-2 and MTPPT in the brain of mouse models of AD.