Targeting REV-ERB to treat Alzheimer's disease

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 记忆丧失、认知障碍和痴呆。根据 2017 年阿尔茨海默病数据 AD 是美国第六大死因，今年将给国家造成 2590 亿美元的损失 年。目前有超过 500 万美国人患有 AD，预计这一数字还会增加 到 2050 年，这一数字将达到 1600 万。目前治疗 AD 的疗效非常有限，因此存在 迫切需要改进的药物治疗。 AD的特点是形成老年性 受影响个体灰质中的斑块和神经原纤维缠结。老年斑是 由不溶性淀粉样β (Aβ) 肽的细胞外沉积组成，这些肽通常与 含有丰富的小胶质细胞（大脑驻留巨噬细胞）和星形胶质细胞。人们普遍认为， Aβ的细胞外积累是AD发病机制的关键事件。引起的炎症 Aβ 的积累被认为是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上是 AD 发病机制的基础。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少神经炎症并改善认知能力 AD 模型中的函数。该项目的目标是开发优化的 REV-ERB 激动剂， 治疗阿尔茨海默病和其他潜在疾病时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。

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.