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

• 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
• 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' s Disease; Alzheimer' 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

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

Beyond Trisomy 21: Phenotypic Variability in People with Down Syndrome Explained by Further Chromosome Mis-segregation and Mosaic Aneuploidy.

超越 21 三体：唐氏综合症患者的表型变异通过进一步的染色体错误分离和嵌合非整倍性来解释。

• DOI: 10.4172/2472-1115.1000109
• 发表时间: 2016
• 期刊: Journal of Down Syndrome & chromosome abnormalities
• 作者: Potter,Huntington

Transfection by electroporation.

• DOI: 10.1002/0471142727.mb0903s62
• 发表时间: 2003-05-01
• 期刊: Current protocols in molecular biology
• 作者: Potter, Huntington

David H. Dressler 1941-2014.

大卫·H·德雷斯勒，1941-2014。

• DOI: 10.1038/ng.3099
• 发表时间: 2014
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Potter,Huntington

Kinesin light chain-1 variant E disrupts axonal transport and Aβ generation in Alzheimer's disease (comment on DOI 10.1002/bies.201400131).

驱动蛋白轻链 1 变体 E 破坏阿尔茨海默病中的轴突运输和 Aβ 生成（DOI 10.1002/bies.201400131 的评论）。

• DOI: 10.1002/bies.201400206
• 发表时间: 2015
• 期刊: BioEssays : news and reviews in molecular, cellular and developmental biology
• 作者: Potter,Huntington

Exosomal biomarkers in Down syndrome and Alzheimer's disease.

• DOI: 10.1016/j.freeradbiomed.2017.08.028
• 发表时间: 2018-01
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Hamlett ED;Ledreux A;Potter H;Chial HJ;Patterson D;Espinosa JM;Bettcher BM;Granholm AC
• 通讯作者: Granholm AC