SIRT3 Deficiency-mediated Metabolic Dysregulation in Comorbid Alzheimer's Disease

SIRT3 缺乏介导的阿尔茨海默病共病代谢失调

• 批准号: 10477264
• 负责人: SUBBIAH PUGAZHENTHI
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477264
• 关键词: APP-PS1; Acceleration; Adult; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Amyloid deposition; Antioxidants; Astrocytes; Brain; CASP1 gene; Calories; Cardiovascular Diseases; Cells; Chronic; Citric Acid Cycle; Consumption; Deacetylase; Deacetylation; Dementia; Diabetes Mellitus; Disease; Disease Management; Disease Progression; Down-Regulation; Electron Transport; Enterobacteria phage P1 Cre recombinase; Enzymes; Exposure to; Gene Expression Profile; Goals; Healthcare Systems; Human; Hyperinsulinism; Hypertension; Impaired cognition; Impairment; Individual; Inflammasome; Inflammatory; Insulin Resistance; Insulinase; Interleukin-1 beta; Interleukin-18; Knock-out; Lead; Lesion; Link; Longevity; LoxP-flanked allele; Mediating; Metabolic; Metabolic Marker; Metabolic Pathway; Metabolic stress; Metabolic syndrome; Metabolism; Microglia; Mitochondria; Mitochondrial Proteins; Modeling; Multiprotein Complexes; Mus; Myeloid Cells; Neurons; Obesity; Pathogenesis; Pathology; Pathway interactions; Peripheral; Persons; Phagocytosis; Pharmaceutical Preparations; Phase; Play; Point Mutation; Population; Post-Translational Protein Processing; Predisposition; Proteins; Radial; Research; Respiration; Risk Factors; Role; Sampling; Senile Plaques; Stains; Testing; Tissue-Specific Gene Expression; Tissues; Toxin; Transgenic Mice; Transgenic Organisms; Veterans; age group; amyloid formation; amyloid pathology; aposome; arm; brain cell; brain metabolism; cell type; cognitive function; comorbidity; conditioned fear; cytokine; epidemiology study; fatty acid metabolism; insulin sensitivity; metabolomics; middle age; military veteran; mitochondrial dysfunction; mitochondrial metabolism; mouse model; neurofibrillary tangle formation; neuroinflammation; novel; novel marker; novel therapeutics; progressive neurodegeneration; therapeutic target; transcriptome sequencing; water maze

Alzheimer's disease (AD), the most frequent cause of dementia, is characterized by accumulation of amyloid plaques and formation of neurofibrillary tangles. Treatment of AD is a challenge because this devastating disease often coexists with other brain lesions caused by comorbidities, including obesity, diabetes, hypertension and cardiovascular diseases. Metabolic syndrome (MetS) is the early stage of these comorbidities and it is prevalent among veteran population. MetS in mid-life could interact with the asymptomatic cellular phase of AD and accelerate the disease progression. The role of comorbidities needs to be examined early because the comorbid population may take diverse paths in terms of disease management and the type of medications used. Therefore, epidemiological studies can sometime yield mixed findings in terms of their susceptibility to dementia. Studies of early interactions between MetS and AD, using comorbid models of AD, can identify converging pathways. In MetS, mitochondrial proteins are hyperacetylated, leading to their decreased function. This protein modification is reversed by the deacetylase enzyme, known as SIRT3, the focus of this study. SIRT3 downregulation is a critical component of MetS because (i) global knockout of Sirt3 in mice leads to acceleration of MetS, (ii) reduced human SIRT3 activity, caused by a single point mutation (V208I), is associated with MetS and (iii) chronic consumption of excessive calories, a cause of MetS, decreases SIRT3 levels and activity. While SIRT3 research has generally remained in the domain of peripheral tissues, its function in brain mitochondrial metabolism is beginning to emerge. We recently made the critical observations of hyperacetylation/downregulation of mitochondrial proteins, impaired mitochondrial respiration, and markers of neuroinflammation with the brain samples of Sirt3-/- mice. Therefore, we crossed these mice with Alzheimer's transgenic (APP/PS1) mice to generate APP/PS1/Sirt3-/- mice, as a comorbid AD model with MetS. Exacerbation of insulin resistance, amyloid pathology, neuroinflammation, microglial dysregulation and differential gene expression patterns (RNA-seq analysis) in the brain were observed in these mice. Our preliminary studies suggested that SIRT3 deficiency in MetS may cause metabolic dysregulation and neuroinflammation in midlife and accelerates cognitive decline in individuals susceptible for AD. The overall objective of this study is to dissect the causal mechanisms by examining the roles of SIRT3 deficiency in neurons, astrocytes and microglia of comorboid AD mouse brain. We hypothesize that “SIRT3 deficiency and amyloid pathology interact through converging pathways of metabolic dysregulation and neuroinflammation in comorbid AD”. This hypothesis will be tested with the following Specific Aims: Aim 1. To determine the effects of SIRT3 deficiency on brain mitochondrial metabolism, insulin resistance and cognitive decline in APP/PS1/Sirt3-/- mice, a comorbid AD model Aim 2. To determine the effects of SIRT3 deficiency in different brain cell types on gene expression patterns and markers of metabolic stress in comorbid AD Aim 3. To determine the role of microglial dysregulation as a key component of SIRT3 deficiency- induced neuroinflammation Findings of this study will identify specific mechanisms by which MetS accelerates AD pathogenesis and place mitochondrial protein hyperacetylation upstream of neuroinflammation. Therapeutic targeting of SIRT3 in AD with coexisting pathologies has the potential to produce beneficial effects when combined with treatments that reduce Alzheimer's pathologies.

阿尔茨海默病（AD）是痴呆的最常见原因，其特征在于淀粉样蛋白的积累 斑块和神经纤维缠结的形成。AD的治疗是一个挑战，因为这种毁灭性的疾病 通常与其他由合并症引起的脑部病变共存，包括肥胖、糖尿病、高血压和 心血管疾病代谢综合征（MetS）是这些合并症的早期阶段，并且很普遍 在退伍军人中。中年的MetS可以与AD的无症状细胞期相互作用， 加速疾病的发展。需要早期检查合并症的作用，因为合并症 在疾病管理和使用的药物类型方面，人口可能采取不同的途径。因此，我们认为， 流行病学研究有时会在他们对痴呆症的易感性方面得出不同的结果。研究 使用AD的共病模型，MetS和AD之间的早期相互作用可以鉴定会聚途径。 在MetS中，线粒体蛋白被过度乙酰化，导致其功能降低。这种蛋白质 修饰被称为SIRT 3的脱乙酰酶逆转，这是本研究的重点。SIRT3 下调是MetS的关键组成部分，因为（i）小鼠中Sirt 3的整体敲除导致 MetS的加速，（ii）由单点突变（V208 I）引起的人SIRT 3活性降低， 和（iii）长期消耗过量的卡路里（MetS的一个原因），降低SIRT 3水平， 活动虽然SIRT 3的研究一般仍停留在外周组织领域，但其在脑组织中的功能 线粒体代谢开始出现。我们最近提出了以下重要意见： 线粒体蛋白的乙酰化过度/下调，线粒体呼吸受损，以及 用Sirt 3-/-小鼠的脑样品观察神经炎症。因此，我们将这些小鼠与阿尔茨海默氏症 转基因（APP/PS1）小鼠以产生APP/PS1/Sirt 3-/-小鼠，作为与MetS共病的AD模型。加重 胰岛素抵抗、淀粉样病变、神经炎症、小胶质细胞失调和差异基因 在这些小鼠中观察脑中的表达模式（RNA-seq分析）。 我们的初步研究表明，MetS中SIRT 3的缺乏可能导致代谢失调， 神经炎症，并加速AD易感个体的认知能力下降。整体 本研究的目的是通过检查SIRT 3缺陷在神经元中的作用来剖析因果机制， 星形胶质细胞和小胶质细胞。我们假设“SIRT 3缺陷和淀粉样蛋白 病理学通过代谢失调和神经炎症的会聚途径相互作用， 共病AD”。该假设将通过以下具体目标进行检验： 目标1.为了确定SIRT 3缺乏对脑线粒体代谢的影响，胰岛素 APP/PS1/Sirt 3-/-小鼠（共病AD模型）的抵抗力和认知下降 目标二。确定不同脑细胞类型中SIRT 3缺陷对基因表达的影响 共病AD的代谢应激模式和标志物 目标3.为了确定小胶质细胞失调作为SIRT 3缺陷的关键组成部分的作用， 诱发性神经炎症 这项研究的结果将确定具体的机制，代谢S加速AD的发病机制和地方 线粒体蛋白质高度乙酰化上游的神经炎症。SIRT 3在AD中的治疗靶向 与共存的病理学结合时， 减少阿尔茨海默病的发病率。