Abnormal Low Density Lipoprotein Receptor Localization and Function in AD

描述（由申请人提供）：我们试图阐明动脉粥样硬化和Abeta在共病阿尔茨海默病（AD）和血管性痴呆的发病机制中发挥的相互作用。尽管该领域的大部分努力都集中在LDL、ApoE及其受体在AD发病机制中的作用上，但我们已经获得了证据，即APP/Abeta改变了LDLR的表达和定位，使得其集中在单个核周聚集体中，而不是分选到细胞表面。其他实验表明，Abeta诱导MT网络中的一般缺陷，这可能导致一些但不是所有膜蛋白（包括LDLR）的错误定位，可能使其活性降低。因此，我们建议测试假设1。APP/Abeta影响LDLR表达和细胞内定位。 2. A β诱导的LDLR错误定位导致LDLR功能缺陷、高脂血症和动脉粥样硬化。所提出的实验是重要的，因为它们可以使我们得出结论，动脉粥样硬化，特别是在大脑中经常伴随AD的一个原因是因为它是由Abeta诱导的LDLR功能缺陷促进的。此外，当LDLR活性较低时，ApoE的不同亚型对LDLR的亲和力/活化的差异可能变得更加严重，因此部分解释了ApoE 4引起的AD风险增加。这些发现和结论形成了一系列综合实验的基础，以测试上述假设，并确定Abeta是否诱导AD中其他重要的神经元和非神经元蛋白的错误分类和功能失活，特别是生长因子受体和胰岛素受体。

DESCRIPTION (provided by applicant): We seek to elucidate the interactive roles that atherosclerosis and Abeta play in the pathogenesis of co-morbid Alzheimer's disease (AD) and vascular dementia. Although, most of the field's efforts have been focused on the role of LDL, ApoE and their receptors play in AD pathogenesis, we have obtained evidence that APP/Abeta alters the expression and localization of the LDLR, such that it becomes concentrated in single perinuclear aggregate, rather than sorting to the cell surface. Other experiments suggest that Abeta induces a general defect in the MT network that likely leads to the mis-localization of some, but not all membrane proteins, including the LDLR, potentially rendering it (them) less active. We therefore propose to Test the Hypotheses that 1. APP/Abeta affects LDLR expression and intracellular localization. 2. Abeta-induced LDLR mis-localization leads to LDLR functional deficits, hyperlipidemia and atherosclerosis. The proposed experiments are significant because they may allow us to conclude that one reason why atherosclerosis, especially in the brain so often accompanies AD is because it is promoted by LDLR functional deficits induced by Abeta. Furthermore, the differences in affinity/activation of the different isoforms of ApoE for LDLR may be made more acute when the LDLR is less active, thus accounting in part for the increased risk of AD imparted by ApoE4. These findings and conclusions form the foundation for a comprehensive series of experiments to test the above hypotheses and determine whether Abeta induces the mis-sorting and functional inactivity of other important neuronal and non-neuronal proteins in the AD, particularly, growth factor receptors and the insulin receptor.