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）病例是偶发性的，但有些病例是以常染色体显性遗传的方式遗传的，称为家族性AD（FAD）。这些病例与散发性AD有许多共同的临床和病理特征，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）基因突变是早发性FAD最常见的原因。虽然比老年斑和神经纤维缠结研究较少，但AD也伴有微血管病理学。我们已经在两种含有PS1 FAD突变的转基因小鼠中观察到年龄相关的血管病理学，其类似于人类病例中的微血管病理学，并且在淀粉样前体蛋白（APP）FAD突变小鼠中也发现了血管病理学。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的早期增厚有关。我们还发现，缺乏PS1的内皮细胞过度表达纤连蛋白，并且具有增加的1521整合素（主要纤连蛋白受体）水平。因此，这些观察结果表明PS1在内皮细胞中ECM产生的调节中的作用。本应用程序将解决与这些观察相关的三个关键问题。首先，我们将讨论PS1的缺乏如何影响纤连蛋白的产生，具体的假设是，它通过调节整合素相关的信号转导。其次，我们将解决PS1以及APP FAD突变体是否改变ECM相关蛋白质的产生的问题，并研究在PS1和APP FAD突变转基因小鼠中观察到的微血管病理学的分子基础。最后，我们将解决的问题，改变ECM的生产可能是一个早期事件的微血管病理的人类散发性AD病例。 公共卫生相关性： 随着退伍军人人口的老龄化，AD等疾病对VA的使命越来越重要。虽然AD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，并且仅不完全了解该病症的病理生理学。本申请的重点在于AD中发现的血管病理学的起源，这将促进对AD相关血管病理学的病理生理学基础的理解，这可能导致对该疾病的新治疗靶标的鉴定。

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.