Validation Studies of CRF Receptor 1 as a Target for AD

 描述（由申请人提供）： 阿尔茨海默病（Alzheimer's disease，AD）是一种与年龄相关的神经退行性疾病，其特征是进行性记忆丧失和认知及行为功能的其他方面的损害。这是最常见的痴呆症，目前约有500万美国人患有这种疾病，预计到2050年这一数字将翻两番。在神经病理学上，AD定义为由β-淀粉样蛋白（Aβ）组成的细胞外斑块和由磷酸化形式的微管相关蛋白tau组成的细胞内神经元缠结（NFT）的积累。三个独立基因的突变与罕见的（<3%的病例）遗传性AD有关。更普遍的，散发性的，形式的原因是未知的，虽然最近的工作涉及环境因素，突出地包括压力，作为促进AD发病机制。例如，最近的流行病学研究表明，倾向于经历“心理困扰”或焦虑的个体与在该维度上得分低的年龄匹配的对照相比，发展AD的风险显著更大。该建议的首要假设是，人类慢性应激暴露会增加AD的风险，这是由于皮质和海马CRF信号系统的应激相关改变。基于我们的初步数据，我们提出这种应激-AD关系的潜在机制是CRFR 1激活对Aβ的调节。

 DESCRIPTION (provided by applicant): Project Summary/Abstract Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and impairments in other aspects of cognitive and behavioral function. It is the most common form of dementia, currently afflicting roughly five million Americans, a number projected to quadruple by 2050. Neuropathologically, AD is defined by the accumulation of extracellular plaques composed of beta-amyloid (Aβ), and intracellular neurofibrillary tangles (NFTs), consisting of phosphorylated forms of the microtubule- associated protein, tau. Mutations in three separate genes have been linked to the rare (<3% of cases), heritable, form of AD. The causes of the far more prevalent, sporadic, form are unknown, though recent work has implicated environmental factors, prominently including stress, as promoting AD pathogenesis. For example, recent epidemiological studies indicate that individuals prone to experience "psychological distress" or anxiety are at substantially greater risk to develop AD as age-matched controls that score low on this dimension. The overarching hypothesis of this proposal is that chronic stress exposure in humans confers increased risk of AD due to stress-associated alterations in the cortical and hippocampal CRF signaling systems. Based on our preliminary data, we propose that a potential mechanism underlying this stress-AD relationship is the modulation of Aβ by CRFR1 activation.