Role of Lifespan Intervention on the Regulation and Progression of Alzheimer's Disease

寿命干预对阿尔茨海默病的调节和进展的作用

• 批准号: 10376882
• 负责人: Stacey J Rizzo
• 金额: $ 99.03万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376882
• 关键词: 2-arachidonylglycerol; 5' -AMP-activated protein kinase; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; American; Anti-Inflammatory Agents; Arachidonic Acids; Astrocytes; Autophagocytosis; Biochemical; Biological Markers; Biological Models; Biology of Aging; Brain; Cardiovascular Diseases; Cells; Clinical Trials; Data; Diabetes Mellitus; Disease; Disease Progression; Endocannabinoids; Enzymes; Evaluation; FRAP1 gene; Genetic; Genetic Models; Genetic Risk; Goals; Immune; Individual; Inflammation; Intervention; Late Onset Alzheimer Disease; Lipase; Longevity; Malignant Neoplasms; Modeling; Molecular; Monoacylglycerol Lipases; Mutation; Neurodegenerative Disorders; Neurons; Onset of illness; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Population; Pre-Clinical Model; Prevalence; Prevention; Process; Prophylactic treatment; Protein Kinase; Public Health; Regulation; Research; Role; Signal Transduction; Sirolimus; Symptoms; TREM2 gene; Testing; Therapeutic; Therapeutic Agents; apolipoprotein E-4; attenuation; cell type; comorbidity; disorder prevention; early onset; experimental study; genetic approach; genetic risk factor; healthspan; healthy aging; high risk; immunoregulation; improved; inhibitor; innovation; insight; mTOR Inhibitor; mTOR inhibition; mouse model; neuroinflammation; neuroprotection; normal aging; novel; novel therapeutic intervention; novel therapeutics; prevent; prophylactic; risk variant; systemic inflammatory response; tool

Project Summary/Abstract Our long-term goal is to identify therapeutic agents that can prevent the pathogenesis of Alzheimer’s disease (AD). The number of AD cases is rising dramatically worldwide, and there is an urgent need to develop new therapies that are more efficacious than the four currently approved drugs for AD which provide only modest symptomatic relief. Every clinical trial to date has failed to demonstrate disease-modifying efficacy for AD, which may in part be due to our limited understanding of the mechanisms that precede the pathogenesis of AD, and that are distinct from normal healthy aging. The overall aims of our proposal are to further understand the mechanisms underlying dysregulation of the autophagy-inflammation network that becomes progressively dysregulated with age, and accelerated by pathological conditions. Systemic inflammation is a biomarker of this dysregulation, as exemplified by its prevalence in many aging-related disorders including cardiovascular disease, diabetes, cancers, and neuroinflammation in neurodegenerative disorders such Alzheimer’s disease (AD). We hypothesize that mechanisms which drive systemic inflammation are common to both the biology of aging and AD and propose that interventions which target the shared feature of systemic inflammation, via regulation of the autophagy-inflammation network, may have potential as therapeutic agents for the prevention of conversion to disease pathogenesis in AD, as well as improve healthspan and longevity in aging populations. For this proposal we will use a combination of genetic and pharmacological tools to understand which brain specific cell types may be involved in the regulation of the autophagy-inflammation network via both mTOR dependent and mTOR-independent mechanisms that modulate inflammation. Findings from our studies will provide mechanistic insights at a cellular level and innovative therapeutic strategies for further research. Specifically, we will investigate the individual cell types that contribute to the neuroprotective effects of mTOR inhibition in progressive AD, and confirm and extend the data on the beneficial effects of lifespan and healthspan in sporadic AD with prophylactic treatment of rapamycin. Critically, since age and genetics are the leading risk factors for AD, we will evaluate interventions in preclinical model systems that incorporate both aging and genetic risk factors for AD. We will therefore test the role of direct manipulation of AMPK on modulation of lifespan and healthspan in normal aging and in AD susceptible models, and the beneficial role of MAG lipase inhibition in normal healthy aging and in the pathogenesis of AD in comparison to the effects of rapamycin in a mouse model of late onset AD.

项目摘要/摘要 我们的长期目标是确定可以预防阿尔茨海默氏病发病机理的治疗剂 （广告）。广告案例的数量在全球范围内急剧增加，迫切需要开发新的 疗法比当前仅提供适度的AD的四种药物更有效 有症状的缓解。迄今为止的每项临床试验都未能证明AD的疾病改良效率，这 可能部分是由于我们对AD发病机理的机制的理解有限，并且 与正常健康衰老不同。我们提案的总体目的是进一步了解 自噬炎症网络失调的机制逐渐成为 随着年龄的增长失调，并通过病理条件加速。系统性炎症是这种生物标志物 失调，例如在许多与衰老有关的疾病（包括心血管疾病）中的患病率的体现， 神经退行性疾病中的糖尿病，癌症和神经炎症，例如阿尔茨海默氏病（AD）。我们 假设驱动全身炎症的机制对于衰老的生物学和 广告和提案，通过调节，针对系统感染共享特征的干预措施 自噬炎症网络可能具有预防转化率的治疗剂的潜力 在AD中的疾病发病机理，并改善衰老人群的健康状况和寿命。为了这 提案我们将使用遗传和药物工具的组合来了解哪种脑特异性细胞 通过MTOR依赖性和 调节注射的MTOR独立机制。我们研究的发现将提供机制 在细胞水平和创新的治疗策略上进行进一步研究的见解。具体来说，我们会的 研究有助于MTOR抑制作用的单个细胞类型 进行性广告，并确认并扩展有关零星寿命和健康状况的有益影响的数据 雷帕霉素预防性治疗的AD。至关重要的是，由于年龄和遗传学是领先的风险因素 AD，我们将评估临床前模型系统的干预措施，这些系统既包括衰老和遗传风险 AD的因素。因此，我们将测试直接操纵AMPK在调节寿命和寿命调节中的作用 在正常衰老和AD易感模型中的HealthSpan，以及MAG脂肪酶抑制的有益作用 与雷帕霉素在小鼠模型中的作用相比，正常健康衰老和AD发病机理 迟到广告。