Metabolic syndrome impairs oligodendrocyte metabolic support of neurons leading to Alzheimer’s disease/Alzheimer’s disease and related dementias

代谢综合征损害神经元的少突胶质细胞代谢支持，导致阿尔茨海默病/阿尔茨海默病和相关痴呆症

• 批准号: 10641057
• 负责人: Mohamed Hussein Mohamed Noureldein
• 金额: $ 10.57万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641057
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Bioenergetics; Biological Assay; Brain; Cell Nucleus; Cerebrum; Chromatin; Clinical Research; Coculture Techniques; Cognition; Communication; Data; Dementia; Diabetes Mellitus; Disease; Dyslipidemias; Economic Burden; Elderly; Elements; Ensure; Epigenetic Process; Functional disorder; Future; Gene Delivery; Glycolysis; Goals; Health Care Costs; High Fat Diet; Human; Impaired cognition; Impairment; In Vitro; Insulin Resistance; Intervention; Knock-out; Life; Mediating; Memory; Metabolic; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Mus; Neuronal Injury; Neurons; Obesity; Oligodendroglia; Pathway interactions; Persons; Phase; Physiological; Prevalence; Research; Risk; Role; Signs and Symptoms; Supporting Cell; Testing; Thinness; Transposase; United States; Wild Type Mouse; Work; cognitive function; cost estimate; dementia risk; efficacy evaluation; epigenome; epigenomics; human old age (65+); middle age; multiple omics; neuron loss; new therapeutic target; novel; overexpression; oxidation; pre-clinical research; protective effect; sex; single nucleus RNA-sequencing; socioeconomics; transcriptome; transcriptome sequencing; transcriptomics

ABSTRACT Alzheimer’s disease (AD) and AD-related Dementia (ADRD) constitute the main cause of dementia and mani- fest as an array of symptoms and signs, including impaired cognition and poor memory. AD/ADRD poses a substantial socioeconomic burden, with dementia affecting 1 of 9 people aged 65 and older in 2021 in the United States (US) and direct healthcare costs estimated at $355 billion USD. AD/ADRD currently lacks effec- tive disease-modifying treatments, though multiple AD/ADRD risk factors have been identified, including midlife metabolic syndrome (MetS) and its components, such as diabetes, obesity, and dyslipidemia. Recent preclini- cal and clinical research reveals that AD/ADRD and cognitive impairment associated with MetS progress non- cell autonomously in the brain through a concerted breakdown in oligodendrocyte function with resulting neu- ronal loss. However, there is a gap in our understanding of how MetS and its associated oligodendrocyte dys- function leads to cognitive impairment and AD/ADRD. Given the increasing burden of AD/ADRD and MetS, there is a critical need to identify the mechanisms of oligodendrocyte-neuron metabolic crosstalk and its role in MetS leading to AD/ADRD. Our proposal will elucidate how midlife MetS onset disrupts oligodendrocyte me- tabolism and consequent support to neurons, leading to AD/ADRD in later life. Under physiological conditions, oligodendrocytes metabolically support neurons with lactate shuttled via monocarboxylate transporter 1 (MCT1). This ensures an adequate energy substrate supply to neurons, supporting normal cognitive function. Two crucial pieces of data are relevant to this proposal. First, the MetS influences epigenetic elements that de- crease MCT1 expression. Second, AD/ADRD is associated with oligodendrocyte loss, reduced cerebral lac- tate, and neuronal injury. Our objective therefore is to elucidate the role of oligodendrocyte-neuron metabolic crosstalk and the lactate shuttle in the MetS leading to AD/ADRD with aging. Our central hypothesis is that MetS disrupts oligodendrocyte-neuron metabolic crosstalk, impairing the lactate shuttle, leading to loss of met- abolic support to neurons, ultimately promoting AD/ADRD. We will test our hypothesis by: 1) assessing the ef- fects of MetS on cognition and oligodendrocytes epigenomics and transcriptomics in middle-aged mice, 2) evaluating oligodendrocyte-neuron metabolic crosstalk in an in vitro MetS model, and 3) assessing the impact of targeting the oligodendrocyte lactate shuttle on cognition in middle-aged MetS mice. This study will have a significant impact by elucidating the contribution of oligodendrocyte metabolic support to neurons, particularly via the lactate shuttle, in MetS-associated AD/ADRD, and further examine oligodendrocyte MCT1 as a novel therapeutic target for MetS-associated AD/ADRD. These studies will support our long-term goal of identifying and implementing novel, translatable interventions for MetS-induced AD/ADRD.

抽象的 阿尔茨海默氏病（AD）和与AD相关的痴呆（ADRD）构成了痴呆和疾病的主要原因 节日是一系列符号和标志，包括认知和记忆力不佳。广告/ADRD位置a 实质性的社会经济伯恩（Burnen），痴呆症影响了2021年65岁以上的9人中的1人 美国（美国）和直接医疗保健费用估计为3550亿美元。广告/adrd目前缺乏效率 - 尽管已经确定了多个AD/ADRD风险因素，但包括中年，疾病改良治疗 代谢综合征（MetS）及其成分，例如糖尿病，肥胖和血脂异常。最近的前线 - CAL和临床研究表明，与Mets相关的AD/ADRD和认知障碍 细胞通过少突胶质细胞功能的一致分解在大脑中自主自主 罗纳尔损失。但是，我们对大都会及其相关的少突胶质细胞的理解存在差距 - 功能会导致认知障碍和AD/ADRD。鉴于广告/ADRD和Mets的燃烧越来越大， 迫切需要确定少突胶质细胞 - 神经元代谢串扰的机制及其在 大都会导致广告/adrd。我们的建议将阐明中年大都会的发作如何破坏少突胶质细胞 - Tabolism和随之而来的对神经元的支持，导致后来的AD/ADRD。在身体状况下， 通过单羧酸盐转运蛋白1 （MCT1）。这样可以确保为神经元提供足够的能量底物供应，从而支持正常的认知功能。 两个至关重要的数据与该提案有关。首先，大都会会影响表观遗传因素 折痕MCT1表达。其次，AD/ADRD与少突胶质细胞损失有关，大脑lac降低 泰特和神经元损伤。因此，我们的目标是阐明少突胶质细胞 - 尼尔元代谢的作用 大都会大都会队的串扰和赛车班车，导致AD/ADRD随着衰老而导致广告/ADRD。我们的中心假设是 大都会大都会（Mets 对神经元的支持，最终促进AD/ADRD。我们将通过：1）评估EF-来检验我们的假设 中年小鼠的认知和少突胶质细胞的转录组学和转录组学的事实，2） 评估体外METS模型中的少突胶质细胞 - 神经元代谢串扰，3）评估影响 靶向中年大都会小鼠认知的寡胶质细胞乳酸班车。这项研究将有一个 通过阐明少突胶质细胞代谢对神经元的贡献，特别是 通过鞋底班车，在与MetS相关的AD/ADRD中，并进一步检查少突胶质细胞MCT1作为一种新颖 与MetS相关的AD/ADRD的治疗靶标。这些研究将支持我们确定的长期目标 并针对Mets引起的AD/ADRD实施新颖的，可翻译的干预措施。