Exercise Mimetics for Dementia and Alzheimer's Disease

治疗痴呆和阿尔茨海默病的模拟运动

• 批准号: 10586188
• 负责人: Thomas P Burris
• 金额: $ 226.29万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586188
• 关键词: Address; Adult; Affect; Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; American; Amyloid beta-Protein; Animal Model; Applications Grants; Astrocytes; Biochemical; Brain; Cell Line; Cell Respiration; Cells; Chemicals; Clinical; Cognition; Cytoskeletal Proteins; Data; Dementia; Deposition; Development; Disease; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Exercise; Genetic Transcription; Goals; Hippocampus; Impaired cognition; Impairment; Independent Living; Individual; Knockout Mice; Language; Learning; Ligand Binding; Ligands; Macrophage; Memory; Memory Loss; Metabolic; Metabolism; Microglia; Modeling; Motor; Mus; Names; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nuclear Orphan Receptor; Nuclear Receptors; Orphan; Oxidative Regulation; Peripheral; Pharmaceutical Chemistry; Play; Process; Property; Research; Role; Scheme; Senile Plaques; Skeletal Muscle; Tissues; abeta deposition; aged; amyloid precursor protein processing; clinical candidate; cognitive enhancement; cognitive function; design; drug discovery; estrogen-related receptor; executive function; extracellular; gray matter; human old age (65+); hyperphosphorylated tau; improved; mimetics; mouse model; neurocognitive disorder; neurogenesis; novel therapeutics; pharmacologic; receptor; research clinical testing; social cognition; tool; xenoestrogen

Project Summary Dementia or major neurocognitive disorder is a condition of significant cognitive decline that impairs independent living. Learning and memory, executive function, perceptual-motor function, social cognition, and language may be affected. Although dementia is typically associated with aging, it is not a natural component of the aging process. Dementia is associated with several diseases, but most commonly associated with AD (60-80%). AD is a progressive neurodegenerative disease with clinical features that include memory loss, cognitive impairment and dementia. More than 5 million Americans currently live with AD and it is expected to increase to as much as 16 million by 2050. Ten percent of individuals over the age of 65 in the U.S. currently have AD. Current treatments for AD have limited efficacy and there is a significant need for improved pharmacological therapies. AD is characterized by the formation of senile plaques and neurofibrillary tangles in the grey matter of affected individuals. The senile plaques are composed of extracellular deposition of insoluble amyloid beta (Aβ) peptides that are typically associated with a wealth of microglia (brain resident macrophages) and astrocytes. ERRs are orphan receptors that play a key role in regulation of oxidative metabolism, and we have discovered that they function as exercise mimetics and enhance cognitive function in normal and aged mice as well as decrease amyloid plaques in animal models of AD. The goal of this project is to develop optimized ERR agonists that may be effective agents in treatment of dementia and Alzheimer's disease.

项目概要 痴呆症或主要神经认知障碍是一种认知能力显着下降的病症，会损害 独立生活、学习和记忆、执行功能、知觉运动功能、社会认知和 尽管痴呆症通常与衰老有关，但它并不是自然因素。 痴呆症与多种疾病有关，但最常见的是与 AD 相关。 (60-80%) AD 是一种进行性神经退行性疾病，其临床特征包括记忆丧失、 目前有超过 500 万美国人患有 AD，并且预计将出现这种情况。 到 2050 年，这一数字将增至 1600 万。目前，美国 65 岁以上人口中有 10% 患有 AD 的患者目前的治疗效果有限，因此迫切需要改进。 AD的特征是老年斑和神经原纤维缠结的形成。 受影响个体的灰质由细胞外沉积物组成。 不溶性淀粉样β (Aβ) 肽通常与大量小胶质细胞（大脑驻留细胞）相关 巨噬细胞和星形胶质细胞是孤儿受体，在氧化调节中发挥关键作用。 新陈代谢，我们发现它们可以起到运动模拟的作用，并增强认知功能 该项目的目标是减少正常和老年小鼠的 AD 动物模型中的淀粉样斑块。 开发优化的 ERR 激动剂，可能成为治疗痴呆和阿尔茨海默病的有效药物 疾病。