Mechanisms Underlying the Vascular Pathology of Alzheimer's Disease

描述(由申请人提供)： 虽然大多数阿尔茨海默病(AD)病例是零星发生的，但也有一些是以常染色体显性遗传方式遗传的，被称为家族性AD(FAD)。这些病例具有许多散发性阿尔茨海默病的临床和病理特征，但发病年龄要早得多。尽管它们相对罕见，但已知的遗传病因学使它们成为转基因动物建模的理想选择，人们希望他们的研究将为更常见的散发性疾病中受到干扰的分子途径提供线索。早老素-1(PS1)基因突变是公认的早发性FAD最常见的原因。虽然对AD的研究比老年斑和神经原纤维缠结要少，但AD也伴有微血管病变。我们在两组携带PS1 FAD突变的转基因小鼠中观察到了与年龄相关的血管病理，这与人类的微血管病理相似，在淀粉样前体蛋白(APP)FAD突变小鼠中也发现了血管病理。PS1小鼠的病理与几种细胞外基质(ECM)相关蛋白的异常表达和血管基底层早期增厚有关。我们还发现，缺乏PS1的内皮细胞过度表达纤维连接蛋白，并增加了主要的纤维连接蛋白受体1521整合素的水平。因此，这些观察结果表明PS1在调节内皮细胞中ECM的产生中起作用。本申请将解决与这些观察结果相关的三个关键问题。首先，我们将阐述PS1的缺失如何影响纤维连接蛋白的产生，具体假设是它通过调节整合素相关信号来实现这一点。其次，我们将讨论PS1和APP Fad突变是否会改变ECM相关蛋白的产生，并检测在PS1和APP Fad突变转基因小鼠中观察到的微血管病理的分子基础。最后，我们将讨论ECM产生的改变是否可能是散发性AD患者微血管病变的早期事件。 公共卫生相关性： 随着退伍军人人口的老龄化，阿尔茨海默病等疾病对退伍军人管理局的使命变得越来越重要。虽然阿尔茨海默病的临床特征和病理学是众所周知的，但没有有效的治疗方法，而且对该病的病理生理学也只有不完全的了解。目前对AD血管病理起源的研究将促进对AD相关血管病理学的病理生理学基础的理解，从而可能导致对AD疾病新的治疗靶点的确定。

DESCRIPTION (provided by applicant): While most cases of Alzheimer's disease (AD) occur sporadically, some are inherited in an autosomal dominant fashion and known as familial AD (FAD). These cases share many clinical and pathological features found in sporadic AD but exhibit a much earlier age of onset. Despite their relative rarity, their known genetic etiology makes them ideal for modeling in transgenic animals and it is hoped that their study will provide clues to the molecular pathways that are disturbed in the more common sporadic disease. Mutations in the presenilin-1 (PS1) gene are the most commonly recognized cause of early onset FAD. Although less studied than senile plaques and neurofibrillary tangles, AD is also accompanied by microvascular pathology. We have observed an age related vascular pathology in two lines of transgenic mice harboring PS1 FAD mutations that resembles the microvascular pathology in human cases and vascular pathology is also found in amyloid precursor protein (APP) FAD mutant mice. The pathology in the PS1 mice is associated with abnormal expression of several extracellular matrix (ECM) related proteins and early thickening of the vascular basal laminae. We have also found that endothelial cells that lack PS1 overexpress fibronectin as well as have increased levels of the 1521 integrin, the principle fibronectin receptor. These observations thus suggest a role for PS1 in the regulation of ECM production in endothelial cells. This application will address three key questions related to these observations. Firstly we will address how the absence of PS1 affects production of fibronectin with the specific hypothesis that it does so by regulating integrin related signaling. Secondly we will address the question of whether PS1 as well as APP FAD mutants alter ECM related protein production and examine the molecular basis of the microvascular pathology observed in PS1 and APP FAD mutant transgenic mice. Finally we will address the question of whether altered ECM production may be an early event in the microvascular pathology of human cases of sporadic AD. PUBLIC HEALTH RELEVANCE: With the aging of the veteran population diseases such as AD are becoming of increasing importance to the mission of the VA. While the clinical features and pathology of the AD are well known, there are no effective treatments and the pathophysiology of the disorder is only incompletely understood. The present application with its focus on the origins of the vascular pathology found in AD will advance understanding of the pathophysiological basis of AD associated vascular pathology which may lead to the identification of new therapeutic targets for the disease.