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.

摘要 阿尔茨海默病（AD）和AD相关性痴呆（ADRD）构成痴呆和躁狂的主要原因。 一系列症状和体征，包括认知受损和记忆力差。AD/ADRD构成一个 严重的社会经济负担，到2021年， 美国（US）和直接医疗费用估计为3550亿美元。AD/ADRD目前缺乏有效的 尽管已经确定了多种AD/ADRD风险因素，包括中年， 代谢综合征（MetS）及其组分，如糖尿病、肥胖症和血脂异常。最近的预斜- 临床研究表明，AD/ADRD和与代谢综合征相关的认知障碍进展非 细胞自主地在大脑中通过协调的少突胶质细胞功能的崩溃， 罗纳尔损失然而，我们对MetS及其相关少突胶质细胞如何变性的理解存在差距。 功能导致认知障碍和AD/ADRD。鉴于AD/ADRD和MetS的负担日益增加， 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 MetS导致AD/ADRD。我们的建议将阐明中年MetS发作如何破坏少突胶质细胞的代谢， 禁忌症和随之而来的支持神经元，导致AD/ADRD在以后的生活。在生理条件下， 少突胶质细胞通过单羧酸转运体1代谢乳酸支持神经元 （MCT 1）。这确保了足够的能量基质供应给神经元，支持正常的认知功能。 两个关键数据与这一提议有关。首先，MetS影响表观遗传因素， 增加MCT 1表达。第二，AD/ADRD与少突胶质细胞损失、大脑缺乏、 以及神经元损伤。因此，我们的目标是阐明少突胶质细胞-神经元代谢的作用， 串扰和乳酸穿梭在MetS导致AD/ADRD与老化。我们的核心假设是， MetS破坏少突胶质细胞-神经元代谢串扰，损害乳酸穿梭，导致met丢失， 代谢支持神经元，最终促进AD/ADRD。我们将通过以下方式来检验我们的假设：1）评估EF- MetS对中年小鼠认知和少突胶质细胞表观基因组学和转录组学的影响，2） 在体外MetS模型中评估少突胶质细胞-神经元代谢串扰，和3）评估影响 针对少突胶质细胞乳酸穿梭对中年MetS小鼠认知的影响。这项研究将有一个 通过阐明少突胶质细胞代谢支持对神经元的贡献， 通过乳酸穿梭，在代谢综合征相关的AD/ADRD，并进一步研究少突胶质细胞MCT 1作为一种新的 MetS相关AD/ADRD的治疗靶点。这些研究将支持我们的长期目标， 并对MetS诱导的AD/ADRD实施新的、可翻译的干预措施。