Presenilin-1 as an Hypoxia Sensor

描述（由申请人提供）：早老素-1 （PS1）基因突变是家族性阿尔茨海默病（FAD）最常见的原因。尽管它们相对罕见，但它们已知的遗传病因使它们成为转基因动物建模的理想选择，并且希望他们的研究将为更常见的散发疾病中受到干扰的分子途径提供线索。除了老年斑（SPs）和神经原纤维缠结（nft）外，AD大脑还表现出微血管病理。PS1零突变小鼠在发育过程中表现出中枢神经系统的血管缺陷。最近我们发现PS1-/-脑的血管发育可以通过在神经祖细胞中选择性表达PS1来挽救。考虑到脑血管系统的中胚层起源，这一结果令人惊讶，并认为PS1介导了血管发育所需的神经来源信号。PS1 FAD突变转基因小鼠也表现出与年龄相关的血管病理，包括在神经元特异性启动子（NSE）控制下表达FAD突变的小鼠。NSE - FAD小鼠的病理是有趣的，因为转基因不在血管中表达，这提供了一个与胚胎拯救有趣的相似之处，并表明PS1的神经元表达影响成年大脑的血管稳态。在成人组织中，缺氧是血管发育和血管稳态的主要调节因子。最近我们发现缺氧诱导因子1 α (Hif1a)在PS1-/-胚胎中的表达降低，并且PS1-/-神经元和成纤维细胞在体外不能激活Hlf1a。在NSE FAD突变转基因小鼠中，Hlf1a水平也有所下降。这些观察结果使我们假设PS1对Hif1a的激活至关重要，并且在含有PS1 FAD突变体的神经元中，Hif1a的激活可能受损。在这里，我们将通过三个特定的目标来探索这些假设，这些目标旨在确定PS1在缺氧期间对Hif1a激活至关重要的生化基础，确定通过Hif1a信号传导失败是否可能是PS1-/-胚胎血管衰竭的近端原因，并检查通过Hif1a途径的缺氧诱导信号传导是否被PS1 FAD突变体破坏。这项研究的公共卫生意义在于它探索了一个关于神经血管信号的新假设，以及它可能有助于解释这种信号在阿尔茨海默病中如何被破坏的信息。

DESCRIPTION (provided by applicant): Mutations in the presenilin-1 (PS1) gene are the most commonly recognized cause of familial Alzheimer's disease (FAD). 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 as well. Besides senile plaques (SPs) and neurofibrillary tangles (NFTs), AD brain also exhibits a microvascular pathology. PS1 null mutant mice exhibit vascular defects in the CNS during development. Recently we found that vascular development in PS1-/- brain can be rescued by selective expression of PS1 in neural progenitor cells. This rescue was surprising given the mesodermal origins of the cerebral vasculature and argued that PS1 mediates neural derived signals that are required for vascular development. PS1 FAD mutant transgenic mice also exhibit an age-related vascular pathology including mice in which an FAD mutation is expressed under the control of a neuron specific promoter (NSE). The pathology in the NSE FAD mice is intriguing since the transgene is not expressed in blood vessels providing an interesting parallel to the embryonic rescue and suggesting that neuronal expression of PS1 influences vascular homeostasis in adult brain. Hypoxia is a major regulator of vascular development as well as vascular homeostasis in adult tissues. Recently we found that expression of the hypoxia inducible factor 1 alpha (Hif1a) is decreased in PS1-/- embryos and that PS1-/- neurons and fibroblasts fail to activate Hlf1a in vitro. Hlf1a levels are also decreased in NSE FAD mutant transgenic mice. These observations have lead us to postulate that PS1 is essential for Hif1a activation and that Hif1a activation may be impaired in neurons harboring PS1 FAD mutants. Here we will explore these hypotheses through three specific aims directed at defining the biochemical basis for why PS1 is essential for Hif1a activation during hypoxia, determining whether failed signaling through the Hif1a may be a proximal cause of the vascular failure in PS1-/- embryos and examining whether hypoxia-induced signaling through the Hif1a pathway is impaired by PS1 FAD mutants. The public health relevance of this research lies in its exploration of a novel hypothesis concerning neurovascular signaling and the information that it might contribute to how this signaling is disrupted in AD.