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.

项目摘要 痴呆或主要神经认知障碍是一种显著的认知下降的状况， 独立生活。学习和记忆、执行功能、感知运动功能、社会认知和 语言可能会受到影响。虽然痴呆症通常与衰老有关，但它不是一个自然组成部分 衰老过程的一部分。痴呆症与几种疾病有关，但最常见的是与AD有关 （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， 认知障碍和痴呆。目前有超过500万美国人患有AD，预计 到2050年增加到1600万。目前，美国65岁以上的人中有10% 有AD。目前用于AD的治疗具有有限的功效，并且显著需要改进的治疗。 药物治疗AD的特征是老年斑和神经元缠结的形成， 受影响个体的灰质。老年斑是由细胞外沉积的 不溶性淀粉样β（Aβ）肽，通常与大量小胶质细胞（脑内驻留 巨噬细胞）和星形胶质细胞。ERRs是孤儿受体，在调节氧化应激中起关键作用。 代谢，我们已经发现它们作为运动模拟物发挥作用，并增强认知功能， 正常和老年小鼠以及减少AD动物模型中的淀粉样斑块。这个项目的目标是 开发优化的ERR激动剂，可能是治疗痴呆和阿尔茨海默病的有效药物， 疾病