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在阿尔茨海默病(AD)和血管性痴呆的发病机制中所起的交互作用。尽管该领域的大部分工作都集中在低密度脂蛋白、载脂蛋白E及其受体在AD发病机制中的作用，但我们已经获得证据表明，APP/Abeta改变了LDLR的表达和定位，使其集中在单个核周聚集，而不是分选到细胞表面。其他实验表明，Abeta导致MT网络中的一个普遍缺陷，这可能导致一些但不是所有膜蛋白的错误定位，包括LDLR，可能使其活性降低。因此，我们建议检验假设：1.APP/Aβ影响LDLR的表达和细胞内定位。2.Aβ诱导的低密度脂蛋白受体错位导致低密度脂蛋白受体功能障碍、高脂血症和动脉粥样硬化。拟议的实验意义重大，因为它们可能让我们得出结论，动脉粥样硬化，特别是大脑中的动脉粥样硬化如此频繁地伴随着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不那么活跃时，不同的ApoE亚型对LDLR的亲和力/激活的差异可能更加明显，这在一定程度上解释了ApoE4增加AD的风险。这些发现和结论构成了一系列全面实验的基础，以检验上述假设，并确定Abeta是否导致AD中其他重要的神经元和非神经元蛋白质，特别是生长因子受体和胰岛素受体的错误分类和功能停滞。

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.