Mechanisms Underlying the Vascular Pathology of Alzheimer's Disease

项目总结/摘要 虽然大多数阿尔茨海默病（AD）病例是偶发性的，但有些病例是遗传性的。 常染色体显性遗传方式，称为家族性AD（FAD）。这些病例具有许多临床和 在散发性AD中发现的病理特征，但表现出更早的发病年龄。尽管他们 相对罕见，它们已知的遗传病因使它们成为转基因动物模型的理想选择， 希望他们的研究将提供线索的分子途径，被扰乱的更多 常见的散发性疾病。早老素-1（PS1）基因突变是最常见的 是早发性FAD的公认病因。虽然比老年斑和神经胶质瘤的研究少， 缠结，AD还伴有微血管病变。我们观察到一个与年龄有关的 在两个系的转基因小鼠中， 在人类病例中发现微血管病理学，在淀粉样蛋白前体中也发现血管病理学 蛋白（APP）FAD突变小鼠。PS1小鼠的病理学与异常的 几种细胞外基质（ECM）相关蛋白的表达和血管的早期增厚 基片我们还发现缺乏PS1的内皮细胞也过度表达纤连蛋白 同时增加了整合素的水平，整合素是纤连蛋白的主要受体。这些观察结果 因此提示PS1在调节内皮细胞中ECM产生中的作用。本申请 将讨论与这些观察有关的三个关键问题。首先，我们将讨论如何 PS1的缺乏影响纤连蛋白的产生，具体的假设是，它通过以下方式来影响纤连蛋白的产生： 调节整合素相关信号传导。其次，我们将讨论PS1以及 APP FAD突变体改变ECM相关蛋白质的产生，并检查其分子基础。 在PS1和APP FAD突变转基因小鼠中观察到微血管病理学。最后我们将 解决ECM产生改变是否可能是微血管中的早期事件的问题， 散发性AD的人类病例的病理学。

PROJECT SUMMARY/ABSTRACT 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 ¿5¿1 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.