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.

摘要 老年科学是一个多学科领域，研究生物衰老和年龄相关的 疾病通过多种途径传播。这些过程彼此高度集成， 将他们作为一个群体进行治疗可能是开发预防或延缓衰老的有效方法， 相关疾病。阿尔茨海默氏病（AD）是一种与年龄相关的疾病，并且预计随着年龄的增长而增加。 发达国家和发展中国家的老年人人数迅速增加。药理 寻找改善疾病的治疗方法的努力取得了有限的成功，这可能是因为他们专注于 找到针对特定机制的特定药物AD是一种复杂的疾病， 与生物衰老过程一致的机制。因此，老年科学方法成功地 治疗AD是一个合乎逻辑的药理学概念。一种由三种药物组成的鸡尾酒被选中， 在这个提议中的测试是基于在小鼠中建立的抗衰老效果。苯丁酸下调 解折叠蛋白反应并抑制组蛋白脱乙酰酶，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。波糖 作为热量限制模拟物，以增强线粒体效率并抑制氧化应激。的 假设是雷帕霉素、阿卡波糖和苯丁酸的药物鸡尾酒，其靶向多个 与阿尔茨海默病相关的衰老过程将减轻认知功能障碍， 在衰老AD小鼠模型中的神经病理学。目标1将决定老龄化的减缓是否会减缓 在20- 30岁的儿童中，使用3种药物的鸡尾酒疗法可以降低早期AD痴呆和神经病变的发展。 月龄AAV Aβ42/P301 Ltau小鼠。鸡尾酒的贡献将根据以下方面进行评估： 生物利用度，抑制全身性疾病，减轻认知障碍和其他临床和 病理学特征和缺乏毒性。目标2将研究可能增加以下风险的衰老过程： 发展AD，关注炎症、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损伤。目标3将开发一种分子桥， 目的1和2研究作为一种独特的代谢组学方法，显示表型和 老化的过程。将在Aim 1队列的脑和肝脏中开发代谢组学特征。会 这也是一个评估性别、年龄和压力对代谢组学结果影响的机会。的概念 一种可以成功缓解AD的老年科学药物鸡尾酒有望产生重大影响， 对患有痴呆症的早期症状和其他AD相关问题的患者的健康。