A geroscience approach for treating Alzheimer's disease

治疗阿尔茨海默病的老年科学方法

基本信息

批准号：
10667414
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
项目类别：
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/10667414
关键词：
Acarbose Age Age Months Aging Alzheimer&apos s Disease Alzheimer&apos 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 Developing Countries Development Diet Disease Drug Combinations Drug Targeting Elderly Epigenetic Process Event Functional disorder Funding Gender Gene Expression Geroscience Goals Grant Health Hippocampus Histone Deacetylase Inhibitor 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 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 cognitive function cohort comparison control design dietary control drug repurposing intervention effect mTOR inhibition metabolome metabolomics middle age mimetics misfolded protein mitochondrial dysfunction mouse model multidisciplinary neurological pathology neuropathology neurovascular pharmacologic preclinical study prevent proteostasis response screening stem cell self renewal success successful intervention symposium therapy development

项目摘要

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.

抽象的老年科学是一个多学科领域，研究生物衰老与年龄相关之间的关系这些过程彼此高度整合，从而导致疾病的发生。针对他们作为一个群体可能是开发预防或延缓衰老疗法的有效方法。阿尔茨海默病（AD）是一种与年龄相关的疾病，预计会随着年龄的增长而增加。发达国家和发展中国家的老年人口数量均迅速增加。寻找疾病缓解疗法的努力取得了有限的成功，可能是因为他们的重点是 AD 是一种涉及多种疾病的复杂疾病。因此，老年科学的方法与生物衰老过程相一致。治疗 AD 是一个合乎逻辑的药理学概念，已选择了三种重新利用药物的混合物。该提案中的测试基于已确定的小鼠抗衰老作用。未折叠的蛋白质反应并抑制组蛋白脱乙酰酶，从而上调抗炎分子。 Rapamycin 抑制 mTOR，增强血管内皮细胞功能并激活阿卡波糖。作为热量限制模拟物，提高线粒体效率并抑制氧化应激。假设是雷帕霉素、阿卡波糖和苯丁酸的药物混合物，针对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衰老 AD 小鼠模型的神经病理学结果将确定衰老速度是否会减慢。使用 3 种药物鸡尾酒在 20 年内减缓早期 AD 痴呆和神经损伤的发展月龄 AAV Aβ42/P301Ltau 小鼠将根据与 AAV Aβ42/P301Ltau 小鼠的关系评估鸡尾酒的贡献。生物利用度、抑制全身性疾病、缓解认知障碍等临床和目标 2 将研究可能增加风险的衰老过程。发展 AD，重点关注炎症、自噬损伤、胰岛素/线粒体功能障碍和目标 3 将为氧化应激、表观遗传功能障碍和血管损伤建立分子桥梁。目标 1 和 2 研究作为显示表型和表型之间关系的独特代谢组学方法将在 Aim 1 队列中开发大脑和肝脏的代谢组学特征。也是评估性别、年龄和压力对代谢组学结果影响的机会。一种能够成功缓解 AD 的老年科学药物鸡尾酒预计将产生重大影响患有痴呆症早期症状和其他 AD 相关问题的患者的健康。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The viral hypothesis: how herpesviruses may contribute to Alzheimer's disease.

病毒假说：疱疹病毒如何导致阿尔茨海默病。

DOI：
发表时间：
2021-10
期刊：
影响因子：
11
作者：
Wainberg, Michael;Luquez, Tain;Koelle, David M;Readhead, Ben;Johnston, Christine;Darvas, Martin;Funk, Cory C
通讯作者：
Funk, Cory C

Short-term oral rapamycin prevents age-related learning impairment in mice.

短期口服雷帕霉素可预防小鼠与年龄相关的学习障碍。

DOI：
发表时间：
2020-09-29
期刊：
影响因子：
0
作者：
Lei, Haoyi;Wang, Juan;Ladiges, Warren;Jiang, Zhou
通讯作者：
Jiang, Zhou

Therapeutic Targeting of Histone Deacetylation to Prevent Alzheimer’s Disease

组蛋白脱乙酰化治疗靶向预防阿尔茨海默病

DOI：
发表时间：
2021-04-26
期刊：
eMedical research
影响因子：
0
作者：
Sophia Chacko;Warren Ladiges
通讯作者：
Warren Ladiges

The neurons that drive infradian sleep-wake and mania-like behavioral rhythms.

驱动红外线睡眠-觉醒和躁狂样行为节律的神经元。

DOI：
发表时间：
2023-11-16
期刊：
影响因子：
0
作者：
Markam, Pratap S;Bourguignon, Clément;Zhu, Lei;Darvas, Martin;Sabatini, Paul V;Kokoeva, Maia V;Giros, Bruno;Storch, Kai
通讯作者：
Storch, Kai

A mouse model of naturally occurring age-related cognitive impairment.

自然发生的与年龄相关的认知障碍的小鼠模型。