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

基本信息

批准号：
10847321
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
项目类别：
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/10847321
关键词：
APP-PS1 Acceleration Adult Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient 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 IL18 gene Impaired cognition Impairment Individual Inflammasome Inflammatory Insulin Resistance Insulinase Interleukin-1 beta Knock-out 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 Proliferating Proteins Radial Research Respiration Risk Factors Role Sampling Senile Plaques Stains Testing Time Tissue-Specific Gene Expression Tissues Toxin Transgenic Mice Transgenic Organisms Veterans abeta accumulation age group amyloid formation amyloid pathology aposome arm biomarker identification 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

项目摘要

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.

阿尔茨海默氏病（AD）是痴呆症最常见的原因，其特征是淀粉样蛋白的积累斑块和神经纤维缠结的形成。 AD治疗是一个挑战，因为这种毁灭性疾病通常与其他合并症引起的其他脑病变并存，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，很普遍在退伍军人中。中年中的大都能群体可能与AD的无症状细胞相相互作用加速疾病进展。合并症的作用需要提早检查，因为合并症人口在疾病管理和所使用的药物类型方面可能采取多种途径。所以，流行病学研究有时会从痴呆症的敏感性方面产生混合的发现。研究使用AD的合并模型，Mets和AD之间的早期相互作用可以识别收敛的途径。在MetS中，线粒体蛋白是过度乙酰化的，导致其功能降低。该蛋白质该研究的重点被脱乙酰基酶（称为SIRT3）逆转。 SIRT3 下调是Mets的关键组成部分，因为（i）小鼠中SIRT3的全局敲除导致由单点突变引起的MetS的加速度（II）降低的人类SIRT3活性（V208i）是相关的 Mets和（iii）长期消费过量卡路里，这是Mets的原因，降低了SIRT3水平和活动。虽然SIRT3研究通常保留在外围组织的领域，但其功能在大脑中的功能线粒体代谢开始出现。我们最近对线粒体蛋白的高乙酰化/下调，线粒体呼吸受损和标记 SIRT3 - / - 小鼠的脑样本的神经炎症。因此，我们用阿尔茨海默氏症越过这些小鼠转基因（APP/PS1）小鼠生成App/ps1/sirt3 - / - 小鼠，作为带有MetS的合并广告模型。恶化胰岛素抵抗，淀粉样病理学，神经炎症，小胶质细胞失调和差异基因在这些小鼠中观察到大脑中的表达模式（RNA-seq分析）。我们的初步研究表明，Mets中的SIRT3缺乏可能会导致代谢失调和中年的神经炎症并加速了容易患AD的个体的认知能力下降。总体这项研究的目的是通过检查SIRT3缺乏在神经元中的作用来剖析因果机制，合并AD小鼠大脑的星形胶质细胞和小胶质细胞。我们假设“ SIRT3缺乏症和淀粉样蛋白病理通过代谢失调和神经炎症的融合途径相互作用合并广告”。该假设将以以下特定目的进行检验：目标1。确定SIRT3缺乏对脑线粒体代谢的影响 APP/PS1/SIRT3 - / - 鼠标的阻力和认知下降，合并广告模型目标2。确定不同脑细胞类型中SIRT3缺乏症对基因表达的影响合并广告中代谢压力的图案和标记目标3。确定小胶质失调作为SIRT3缺乏症的关键组成部分的作用诱导神经炎症这项研究的结果将确定MetS加速AD发病机理并位置的特定机制神经炎症上游的线粒体蛋白高乙酰化。 AD中SIRT3的治疗靶向与共存的病理相结合，与减少阿尔茨海默氏症的病理。