Abnormal Low Density Lipoprotein Receptor Localization and Function in AD

AD 中低密度脂蛋白受体定位和功能异常

基本信息

批准号：
8878140
负责人：
Huntington Potter
金额：
$ 30.92万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8878140
关键词：
Abeta synthesis Accounting Acute Affect Affinity Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Apolipoprotein E Atherosclerosis Attention Binding Blood Blood Vessels Brain Brain Diseases Cell surface Cells Cholesterol Cognitive deficits Complex Defect Deposition Development Embryo Feedback Foundations Growth Factor Receptors Health Hepatocyte Human Hyperlipidemia In Vitro Insulin Receptor Knowledge LDL Cholesterol Lipoproteins Lesion Link Lipids Liquid substance Low Density Lipoprotein Receptor Low-Density Lipoproteins Membrane Proteins Microtubules Mus Nature Neurons Organelles Pathogenesis Pathology Patients Peptides Pharmaceutical Preparations Play Protein Isoforms Proteins Risk Factors Role Sampling Series Slice Sorting - Cell Movement System Testing Transgenic Mice Vascular Dementia abeta deposition age related amyloid pathology apolipoprotein E-3 apolipoprotein E-4 base brain cell cost follow-up in vivo mutant overexpression prevent receptor research study

项目摘要

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.

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所起的相互作用。尽管该领域的大部分工作都集中在 LDL、ApoE 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 会引起 MT 网络的普遍缺陷，这可能会导致一些但不是所有膜蛋白（包括 LDLR）的错误定位，从而可能使其活性降低。因此，我们建议检验以下假设：1. APP/Abeta 影响 LDLR 表达和细胞内定位。 2. Abeta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。所提出的实验很重要，因为它们可以让我们得出这样的结论：动脉粥样硬化（尤其是大脑中的动脉粥样硬化）经常伴随 AD 的原因之一是因为 Abeta 诱导的 LDLR 功能缺陷会促进动脉粥样硬化。此外，当 LDLR 活性较低时，不同 ApoE 亚型对 LDLR 的亲和力/激活差异可能会更加明显，从而在一定程度上解释了 ApoE4 导致 AD 风险增加的原因。这些发现和结论构成了一系列综合实验的基础，以检验上述假设并确定 Abeta 是否会诱导 AD 中其他重要神经元和非神经元蛋白的错误分选和功能失活，特别是生长因子受体和胰岛素受体。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exosomal biomarkers in Down syndrome and Alzheimer's disease.

唐氏综合症和阿尔茨海默病的外泌体生物标志物。

DOI：
发表时间：
2018
期刊：
影响因子：
7.4
作者：
Hamlett, Eric D;Ledreux, Aurélie;Potter, Huntington;Chial, Heidi J;Patterson, David;Espinosa, Joaquin M;Bettcher, Brianne M;Granholm, Ann
通讯作者：
Granholm, Ann

Transfection by electroporation.

通过电穿孔转染。