Implications of Metabolic Dysfunction during Thiamine Insufficiency

硫胺素缺乏期间代谢功能障碍的影响

• 批准号: 10586973
• 负责人: Jason A Zastre
• 金额: $ 36.84万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586973
• 关键词: AD transgenic mice; Acquired Immunodeficiency Syndrome; Address; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Apoptotic; Astrocytes; Attenuated; Autopsy; Bioenergetics; Blood; Brain; Cells; Cerebrum; Chronic; Coenzymes; Cognitive; Coupled; Cre driver; Dementia; Deterioration; Diabetes Mellitus; Disease; Energy Metabolism; Ensure; Enzymes; Etiology; Foundations; Future; Gene Expression; Genes; Genetic Transcription; Goals; Grant; Health; Hippocampus; Histologic; Impaired cognition; Impairment; In Vitro; Inflammation; Inflammatory; Investigation; Ischemia; Knock-out; Knowledge; Link; Magnetic Resonance Imaging; Mediating; Mediator; Metabolic; Metabolic Activation; Metabolic Diseases; Metabolic dysfunction; Metabolism; Methodology; Mission; Nerve Degeneration; Nervous System Trauma; Neurodegenerative Disorders; Neuronal Hypoxia; Neurons; Nutritional; Obesity; Outcomes Research; Oxidative Stress; Pathologic; Pathway interactions; Patients; Process; Procollagen-Proline Dioxygenase; Public Health; Publishing; Research; RiboTag; Role; Stress; Supplementation; Testing; Thalamic structure; Therapeutic; Thiamine; Thiamine Pyrophosphate; United States National Institutes of Health; age related; age related neurodegeneration; alcohol use disorder; beta secretase; beta-site APP cleaving enzyme 1; biological adaptation to stress; cell injury; cell type; chronic alcohol ingestion; cofactor; cognitive function; glucose metabolism; hypoxia inducible factor 1; in vivo; insight; knock-down; micronutrient deficiency; molecular phenotype; mouse model; neuropathology; neurotoxicity; prophylactic; prospective; response; therapeutic target; transcription factor; transcriptome sequencing; transcriptomics

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.

项目概要 血液中维生素 B1（硫胺素）水平下降与认知能力下降显着相关 功能，并与促进阿尔茨海默病 (AD) 神经病理学特征相关。 硫胺素是糖酵解代谢网络中的关键酶辅助因子，从根本上讲 维持所有细胞的生物能量和合成代谢需求。 葡萄糖代谢以满足其高能量需求使其特别容易受到TI的影响 与已确定的 AD 病理学一致，TI 会产生脑损伤。 能量代谢低下、炎症、氧化应激以及体内斑块形成增加 海马体、皮质和丘脑，或更具体地说是激活的辅助因子硫胺素。 二磷酸 (TDP) 确保 3 种关键代谢酶 PDH、α-KGDH 和 TKT A 的功能。 低细胞 TDP 水平导致神经元细胞损伤的核心特征是严重缺乏 另外，TKT、PDH、α-KGDH的活性显着降低。 尽管取得了进展，但在死后的阿尔茨海默氏症患者中，它与痴呆症评级密切相关。 硫胺素水平降低与 AD 神经病理学之间的关系，机制 我们已经确定代谢功能障碍是 TI 的结果。 激活缺氧诱导因子 1 α (HIF1α) 该应用程序将检验 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 产生 TI 相关 AD 神经病理学的细胞和区域组织学表现。 计划检验我们的中心假设，从而通过 (1) 实现此应用程序的目标 利用 HIF1α KO 的细胞类型选择性，我们将揭示以下因素的贡献和关系： TI 期间星形细胞和神经元 HIF1α 活性对神经损伤的影响 (2) 使用基于患病的药物。 (3xTgAD) 转基因 AD 小鼠模型，我们将建立 HIF1α 激活作为启动子 硫胺素不足导致淀粉样蛋白生成活性和认知能力下降 (3) 利用。 通过无偏见的转录组分析，我们将确定分级 TI 压力对时间的影响 我们建议确定神经元和星形胶质细胞内 HIF1α 转录活性的贡献。 通过结合使用 RiboTag RNA-Seq 和 MR 等最先进的方法来检测 HIF1α 成像与细胞特异性 Cre 驱动程序相结合，用于 HIF1α 敲除和三重转基因 AD 小鼠 建立 HIF1α 响应代谢低下的慢性激活模型。 微量营养素缺乏将为识别 AD 病因学提供重大转变，并表明可能 限制与年龄相关的认知能力下降的预防策略。