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

阿尔茨海默病中维生素 B1（硫胺素）转运的病理生理学

基本信息

批准号：
10117711
负责人：
HAMID M SAID
金额：
$ 33.09万
依托单位：
SOUTHERN CALIFORNIA INST FOR RES/EDUC
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10117711
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid beta-Protein Animal Model Blood Brain Brain region Cell Respiration Cells Chronic Cognitive deficits Data Diphosphates Disease Energy Metabolism Exposure to Functional disorder Genes Grant Health Homeostasis Human Impairment Inflammatory Interleukin-1 beta Intestines Investigation Laboratories Mediating Micronutrients Mitochondria Molecular Mus Neurodegenerative Disorders Neurofibrillary Tangles Neurons Oxidative Stress Pancreas Parents Pathogenesis Pathology Physiology Play Process Production Role Structure TNF gene Testing Thiamine Thiamine Deficiency Time Transgenic Animals Vitamin Deficiency Vitamins animal tissue brain cell cell type cytokine design glucose metabolism improved mitochondrial dysfunction mouse model neuroinflammation uptake

项目摘要

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.

阿尔茨海默病（AD）是一种神经退行性疾病，其特征是淀粉样蛋白-β肽（Aβ）- 包含斑块、神经原纤维缠结和认知缺陷、氧化应激。 AD 的病理生理学还包括糖代谢降低。神经炎症，与促炎细胞因子（例如 TNF-α、白细胞介素1β)。硫胺素（维生素B1；也被称为“能量维生素”）是正常氧化不可缺少的线粒体中的能量代谢和 ATP 生成；它在减少细胞能量代谢方面也发挥着重要作用。因此，细胞水平缺乏硫胺素会导致氧化能量受损。新陈代谢、细胞 ATP 水平降低以及氧化应激倾向；线粒体功能/结构受损。存在令人信服的证据表明AD中存在硫胺素稳态，并且缺乏维生素会加重疾病病理。脑细胞通过一种特殊的载体介导的过程从血液中获取硫胺素，该过程涉及硫胺素转运蛋白-1和-2（SLC19A2和SLC19A3基因的产物，一旦内化，硫胺素就会被酶促转化为硫胺素焦磷酸 (TPP)。通过另一个涉及线粒体的专门载体介导的过程转运至线粒体 TPP 转运蛋白（MTPPT；SLC25A19 基因的产物）。我们实验室最近的初步研究。与母体 R01 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），长期暴露于促炎细胞因子会导致细胞硫胺素显着抑制根据这些数据，我们得出了硫胺素的吸收以及 TPP 转运到线粒体中的情况。脑细胞的摄取以及随后将 TPP 转运到线粒体中同样受到慢性疾病的影响。暴露于促炎细胞因子，这反过来会导致细胞硫胺素水平不足/不理想。氧化代谢/ATP 生成受损、氧化应激增加以及异常线粒体的功能/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标： 1) 研究表达水平的可能变化 AD患者大脑不同区域的硫胺素转运蛋白SLC19A2、SLC19A3和SLC25A19；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 TPP 转运至线粒体并确定所涉及的分子机制 3) 确定；小鼠模型脑内 THTR-1、THTR-2 和 MTPPT 表达和活性水平的变化公元