Implications of Metabolic Dysfunction during Thiamine Insufficiency

项目摘要 血液中维生素B1(硫胺素)水平的下降与认知能力的恶化显著相关 功能，并与促进阿尔茨海默病(AD)的神经病理标志有关。 硫胺素是糖酵解代谢网络中的一个关键的酶辅助因子，从根本上说 维持所有细胞的生物能量和合成代谢需要。大脑的广泛需求 对于葡萄糖代谢来说，满足其高能量需求使其特别容易受到TI的影响 介导性代谢损伤。与公认的AD病理一致，TI产生大脑 能量低代谢、炎症、氧化应激和体内斑块形成的增加 海马体、皮质和丘脑。硫胺素或更具体地说是激活的辅因子硫胺素 二磷酸确保了三种关键代谢酶的功能，即PDH、α-KGDH和TKT。一个 低细胞TDP水平导致的神经细胞损伤的中心特征是严重的 大脑能量代谢。此外，TKT、PDH、α-KGDH活性显著降低 在死后的阿尔茨海默病患者中，并与痴呆症分级密切相关。然而，尽管取得了进展 探讨硫胺素水平降低与阿尔茨海默病神经病理的关系 缺乏洞察力。我们已经证实，作为TI的结果的代谢功能障碍 激活缺氧诱导因子-1α(HIF1α)。这个应用程序将检验TI的假设 HIF1α介导的代谢激活启动促凋亡和淀粉样蛋白生成过程 制作与阿尔茨海默病相关的神经病理学的细胞和区域组织学表现。我们 计划测试我们的中心假设，从而通过(1)实现本应用程序的目标 利用HIF1KO的细胞类型选择性，我们将揭示αKO的贡献和关系 星形胶质细胞和神经细胞缺氧诱导因子1α活性在经皮神经损伤治疗中的作用(2)使用患病的 (3xTgAD)转基因AD小鼠模型，我们将建立HIF1α激活作为 硫胺素缺乏导致淀粉样蛋白生成活性和认知能力下降。(3)利用 一项无偏见的转录分析，我们将建立分级的TI应激对 HIF1α在神经元和星形胶质细胞内的转录活性。我们建议确定供款 使用包括RiboTag RNA-Seq和MR在内的最先进的方法组合来检测HIF1α Hif1α基因敲除和三重转基因AD小鼠的成像与细胞特异性Cre驱动 模特们。HIF1α慢性激活与低代谢相关 微量营养素缺乏将提供识别AD病因学的重大转变，并提示可能 限制与年龄相关的认知衰退的预防策略。

Project Summary Declining vitamin B1 (thiamine) blood levels significantly correlates with a deterioration in cognitive function and is associated with promoting Alzheimer’s Disease (AD) neuropathology hallmarks. Thiamine is a critical enzyme cofactor within the glycolytic metabolism network that is fundamentally required to sustain the bioenergetic and anabolic needs of all cells. The brain’s extensive requirement for glucose metabolism to satisfy its high energy demand makes it particularly vulnerable to TI mediated metabolic impairment. Congruent with established AD pathology, TI produces cerebral energy hypometabolism, inflammation, oxidative stress, and an increase in plaque formation within the hippocampus, cortex and thalamus. Thiamine or more specifically the activated cofactor, thiamine diphosphate (TDP) ensures the function of 3 key metabolic enzymes, PDH, α-KGDH, and TKT. A central feature for neuronal cell injury as a result of low cellular TDP levels is severe deficits in cerebral energy metabolism. Additionally, the activity of TKT, PDH, α-KGDH are significantly reduced in post-mortem Alzheimer’s patients and strongly correlate with dementia rating. Yet despite progress into the relationship between reduced thiamine levels and the neuropathology of AD, mechanistic insight is lacking. We have established that the metabolic dysfunction as a consequence of TI activates hypoxia inducible factor-1 alpha (HIF1α). This application will test the hypothesis that TI mediated metabolic activation of HIF1α initiates pro-apoptotic and amyloidogenic processes that produce the cellular and regional histological presentation of TI associated AD-neuropathology. We plan to test our central hypothesis and, thereby, accomplish the objective of this application by (1) Employing cell type selectivity of HIF1α KO we will reveal the contribution and relationship of astrocytic and neuronal HIF1α activity during TI on neurological damage. (2) Using a diseased based (3xTgAD) transgenic AD mouse model, we will establish HIF1α activation as an initiator for amyloidogenic activity and cognitive decline as a consequence of thiamine insufficiency. (3) Utilizing an unbiased transcriptomic analysis, we will establish the temporal impact of graded TI stress on HIF1α transcriptional activity within neurons and astrocytes. We propose to establish the contribution of HIF1α by using a combination of state-of-the-art methodology including RiboTag RNA-Seq and MR Imaging coupled with cell specific Cre-drivers for HIF1α knockout and triple transgenic AD mouse models. Establishing chronic activation of HIF1α in response to hypometabolism linked to micronutrient deficiency would provide a significant shift discerning AD etiology and suggest possible prophylactic strategies to limit age-related cognitive decline.