Lead Exposure in a Novel Mouse Model of Neurologic Disease

描述（由申请人提供）：铅（Pb）的环境暴露与晚发性阿尔茨海默病（AD）和痴呆症的风险有关。虽然铅长期以来一直被认为是儿童的神经毒性剂，但最近越来越多的毒理学和流行病学研究表明，累积的环境铅暴露对成人也有毒性，可能是与年龄相关的神经功能障碍的重要因素。这种联系背后的生物学机制尚不清楚。基于有限数量的动物研究，已经提出了这种联系是通过DNA甲基化状态的表观遗传变化，尽管在人类疾病中缺乏这种机制的证据。该提案考虑了另一种可能性，即这种联系是通过铅驱动的神经病理学变化的组合，并且脑血管病理学是这种形式的神经功能障碍的主要贡献者。脑血管病变的数量在所有形式的年龄相关性痴呆中是一个重要的共病。大多数AD患者存在一定程度的共病脑血管病变，尽管有肥胖和T2 DM病史的患者存在大量这种病变。为了研究这个问题，我们建立了一系列基因敲入小鼠，随着年龄的增长，这些小鼠共同发展淀粉样蛋白病理学和脑血管异常。这种新型小鼠模型（db/AD）的最显著特征是其发展出脑血管病理学的显著表型，包括动脉瘤和中风，并且还显示出严重的认知障碍。我们相信，我们已经创建了一个创新的模型，AD与显着的脑血管疾病，一个欠研究的变种有限的治疗方案。独特的db/AD小鼠不过度表达疾病相关蛋白或使用人工启动子系统，使其成为研究疾病中异常基因调控如何影响脑病理学的理想系统。这提供了一个无与伦比的机会来研究，并可能解离铅暴露在不同时间在动物的lifespa的作用，并衡量对神经病理学的最终影响。因此，这项建议旨在回答三个关键问题有关铅暴露和神经系统疾病发生在以后的生活。首先，早期铅暴露是否比成年后更有害？第二，铅是否会通过增加高血压（铅暴露的一个众所周知的结果）而增加脑血管病变（如中风），从而导致晚年认知功能障碍？最后，铅暴露通过影响AD相关基因的表达对AD相关病理的发展有多大影响？我们相信，我们的小鼠模型是唯一适合回答这些问题。该提案的一个主要创新特征是使用具有独特特征的新型小鼠模型，其表现出显著的年龄相关的AD相关淀粉样蛋白沉积、脑血管病理学和认知功能障碍。该项目不仅对预防和治疗与年龄相关的脑血管疾病有明确的意义，而且有可能促进我们对脑血管疾病作为AD脑内合并症的主要潜在原因的理解。

DESCRIPTION (provided by applicant): Environmental exposure to lead (Pb) has been linked to risk of late-onset Alzheimer's disease (AD) and dementia. Although Pb has long been known as a neurotoxic agent in children, a recent and growing body of both toxicological and epidemiological research indicates that cumulative environmental Pb exposure is toxic to adults as well, and may be a significant contributor to age-related neurologic dysfunction. The biological mechanism underlying this link is not known. It has been proposed based on a limited number of animal studies that the linkage is through epigenetic changes in the methylation state of DNA, although evidence for this mechanism in human disease has been lacking. This proposal considers another possibility, that the linkage is through a combination of Pb-driven neuropathologic change, and that cerebrovascular pathology is the major contributor to this form of neurologic dysfunction. The amount of cerebrovascular pathology is a significant co-morbidity in all forms of age-related dementia. Most individuals with AD have some degree of comorbid cerebrovascular pathology, although individuals with a history of obesity and T2DM have substantial amounts of this pathology. To investigate this problem, we created a line of knock-in mice that co-develops amyloid pathology and cerebrovascular abnormalities with increasing age. The most remarkable feature of this novel mouse model (db/AD) is that it develops a striking phenotype of cerebrovascular pathology, including aneurysms and strokes, and also displays a profound cognitive impairment. We believe that we have created an innovative model of AD with significant cerebrovascular disease, an understudied variant with limited treatment options. The unique db/AD mouse does not overexpress disease related proteins or use artificial promoter systems, making it an ideal system for the study of how aberrant gene regulation in disease can influence brain pathology. This presents an unparalleled opportunity to study, and potentially dissociate the role of Pb exposure at different times in an animal's lifespa and gauge the ultimate impact on neuropathology. This proposal thus seeks to answer three key questions relating to Pb exposure and neurologic disease that occurs later in life. First, is early life Pb exposure more damaging than exposure as an adult? Second, can Pb cause late-life cognitive dysfunction by increasing cerebrovascular pathology, such as strokes, through increased hypertension, a well-known outcome of Pb exposure? Finally, how much does Pb exposure affect the development of AD-related pathology by affecting the expression of AD related genes? We believe that our mouse model is uniquely suited to answering these questions. A major innovative feature of this proposal is the use of a novel mouse model with unique features, exhibiting significant age associated AD-related amyloid deposition, cerebrovascular pathology, and cognitive dysfunction. This project not only has clear implications for the prevention and treatment of age-related cerebrovascular disease, but also has the potential to advance our understanding of the major underlying causes of cerebrovascular disease as comorbidity in the AD brain.