A geroscience approach for treating Alzheimer's disease

治疗阿尔茨海默病的老年科学方法

• 批准号: 10383741
• 负责人: Martin C Darvas
• 金额: $ 77.74万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10383741
• 关键词: Acarbose; Age; Age-Months; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-42; Animal Disease Models; Anti-Inflammatory Agents; Autophagocytosis; Awareness; Biological Aging; Biological Availability; Biological Process; Blood Vessels; Brain; Caloric Restriction; Cell physiology; Clinical; Clinical Research; Complex; Dementia; Developed Countries; Developing Countries; Development; Diet; Disease; Drug Combinations; Drug Targeting; Elderly; Epigenetic Process; Event; FRAP1 gene; Functional disorder; Funding; Gender; Gene Expression; Geroscience; Goals; Grant; Health; Hippocampus (Brain); Histone Deacetylase; Homeostasis; Impaired cognition; Impairment; Individual; Inflammation; Insulin; Interest Group; Intervention; Investigation; Lesion; Liver; Metabolism; Mitochondria; Molecular; Mus; Neurologic; Neurons; Outcome; Oxidative Stress; Pathogenicity; Pathologic; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Phenylbutyrates; Physiological; Play; Process; Proteins; Risk; Role; Sampling; Sirolimus; Stress; Symptoms; Systemic disease; Testing; Tissues; Toxic effect; United States National Institutes of Health; Vascular Endothelial Cell; age effect; age related; anti aging; base; cognitive function; cohort; design; dietary control; drug repurposing; intervention effect; metabolome; metabolomics; middle age; mimetics; misfolded protein; mitochondrial dysfunction; mouse model; multidisciplinary; neurological pathology; neuropathology; neurovascular; preclinical study; prevent; proteostasis; response; screening; stem cell self renewal; success; successful intervention; symposium; therapy development

Abstract Geroscience is a multidisciplinary field that examines the relationship between biological aging and age-related diseases through multiple processes. These processes are highly integrated with one another such that targeting them as a group may be an effective approach to developing therapies to prevent or delay age- related disease. Alzheimer's disease (AD) is an age-related disease and is expected to increase with the number of elderly individuals rapidly rising in both developed and developing countries. Pharmacological efforts to find disease-modifying treatments have met with limited success possibly because they have focused on identifying a specific drug that targets a specific mechanism. AD is a complex disease involving numerous mechanisms in line with processes of biological aging. Therefore, a geroscience approach to successfully treating AD is a logical pharmacological concept. A cocktail of three repurpose drugs has been selected for testing in this proposal based on established anti-aging effects in mice. Phenylbutyrate downregulates the unfolded protein response and inhibits histone deacetylase thereby upregulating anti-inflammatory molecules. Rapamycin inhibits mTOR, enhances vascular endothelial cell function and activates autophagy. Acarbose acts as a caloric restriction mimetic to enhance mitochondrial efficiency and suppress oxidative stress. The hypothesis is that a drug cocktail of rapamycin, acarbose, and phenylbutyrate, that targets multiple aging processes associated with Alzheimer's disease will alleviate cognitive dysfunction and neurological pathology in an aging AD mouse model. Aim 1 will determine if a slowdown in aging will slow down the development of early stage AD dementia and neurological lesions using the 3-drug cocktail in 20- month old AAV Aβ42/P301Ltau mice. The contribution of the cocktail will be evaluated in relation to bioavailability, suppression of systemic disease, alleviation of cognitive impairment and other clinical and pathological features, and lack of toxicity. Aim 2 will investigate aging processes that can increase the risk for developing AD, focusing on inflammation, autophagy impairment, insulin/mitochondrial dysfunction and oxidative stress, epigenetic dysfunction, and vascular impairment. Aim 3 will develop a molecular bridge for Aims 1 and 2 studies as a unique metabolomics way of showing the relationship between phenotype and processes of aging. Metabolomic profiles will be developed in brain and liver from Aim 1 cohorts. There will also be an opportunity to assess effect of gender, age, and strain on metabolomics outcomes. The concept of a geroscience drug cocktail that could successfully alleviate AD would be expected to have a significant impact on the health of patients suffering from early symptoms of dementia and other AD related issues.

抽象的 Geroscience是一个多学科领域，研究了生物衰老与年龄相关的关系 通过多个过程疾病。这些过程彼此高度集成 将它们作为一个小组可能是开发预防或延迟年龄的疗法的有效方法 - 相关疾病。阿尔茨海默氏病（AD）是一种与年龄有关的疾病，预计随着该疾病的增加 发展中国家和发展中国家迅速增加的基本个人数量。药理 寻找改良疾病治疗的努力取得了有限的成功，因为它们已经集中 确定针对特定机制的特定药物。广告是一种复杂的疾病，涉及许多 与生物衰老过程一致的机制。因此，一种成功的方法 治疗广告是一个逻辑的药理概念。已经选择了三种复制品的鸡尾酒 根据小鼠的既定抗衰老作用进行该提案中的测试。苯基丁酸下调 展开的蛋白质反应并抑制组蛋白脱乙酰基酶，从而上调抗炎分子。 雷帕霉素抑制MTOR，增强血管内皮细胞功能并激活自噬。 acarbose 充当热量限制，以增强线粒体效率并抑制氧化应激。这 假设是雷帕霉素，阿果霉和苯基丁酸的药物鸡尾酒，它针对多个 与阿尔茨海默氏病有关的衰老过程将减轻认知功能障碍和 衰老的AD小鼠模型中的神经病理学。 AIM 1将确定衰老的放缓是否会减慢 使用3毒鸡尾酒在20- 月大的AAVAβ42/P301LTAU小鼠。鸡尾酒的贡献将与 生物利用度，抑制全身性疾病，缓解认知障碍和其他临床和 AIM 2将调查可以增加风险的老化过程 开发AD，专注于注射，自噬损伤，胰岛素/线粒体功能障碍和 氧化应激，表观遗传功能障碍和血管障碍。 AIM 3将开发一个分子桥 目标1和2研究是一种独特的代谢组学，以显示表型与 衰老过程。 AIM 1队列中将在大脑和肝脏中发展代谢组谱。将有 同样也是评估性别，年龄和应变对代谢组学结果的影响的机会。概念 可以预期可以成功减轻广告的Geroscience药物鸡尾酒会产生重大影响 关于患有痴呆症早期症状和其他AD相关问题的患者的健康。