Targeting REV-ERB to treat Alzheimer's disease

靶向 REV-ERB 治疗阿尔茨海默病

• 批准号: 10675294
• 负责人: Thomas P Burris
• 金额: $ 198.77万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10675294
• 关键词: Targeting; REV; ERB; treat; Alzheimer

Alzheimer's disease (AD) is a progressive neurodegenerative disease with clinical features that include memory loss, cognitive impairment and dementia. According to 2017 data from the Alzheimer's Association, AD is the 6th leading cause of death in the U.S. and will cost the nation $259 billion dollars this year. More than 5 million Americans currently live with the diagnosis of AD and it is expected to increase to as much as 16 million by 2050. Current treatments for AD have very limited efficacy and thus 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. It is generally recognized that the extracellular accumulation of Aβ is a key event the pathogenesis of AD. Inflammation induced by accumulation of Aβ is believed to be a crucial factor underlying the neural dysfunction and microglia and bone marrow derived phagocytes recruited to the plaques are fundamental to the pathogenesis of AD. We discovered that the REV-ERB nuclear receptors play a critical role in regulation of neuroinflammation and that pharmacological activation of REV-ERB effectively reduces neuroinflammation and improves cognitive function in a model of AD. The goal of this project is to develop optimized REV-ERB agonists that may be effective agents for reduction of neuroinflammation in treatment of Alzheimer's disease and, potentially, other neurodegenerative disorders associated with neuroinflammation.

阿尔茨海默病(AD)是一种进行性神经退行性疾病，其临床特征包括 记忆力丧失、认知障碍和痴呆症。根据阿尔茨海默氏症协会2017年的数据 AD是美国第六大死因，今年将使美国损失2590亿美元 年。目前有500多万美国人患有阿尔茨海默病，预计这一数字还会增加 到2050年将增加到1600万。目前治疗AD的方法疗效非常有限，因此存在一种 对改进药物治疗的重大需求。AD的特点是形成老年性痴呆 患者灰质中的斑块和神经原纤维缠结。老年斑块是 由不溶性淀粉样β蛋白(Aβ)的胞外沉积组成，这些多肽通常与 有丰富的小胶质细胞(脑内巨噬细胞)和星形胶质细胞。人们普遍认为， Aβ的胞外蓄积是AD发病机制中的关键事件。引起炎症的原因是 β的积聚被认为是导致神经功能障碍和小胶质细胞的关键因素 骨髓来源的吞噬细胞聚集到斑块中是AD发病的基础。我们 发现REV-ERB核受体在调节神经炎症和 REV-ERB的药理激活可有效减轻神经炎症和改善认知 在AD模型中发挥作用。该项目的目标是开发优化的REV-ERB激动剂，可能是 治疗阿尔茨海默病和其他潜在疾病中减少神经炎症的有效药物 与神经炎症相关的神经退行性疾病。