Is There a Link Between Alzheimer's and Atheroclerosis

阿尔茨海默病和动脉粥样硬化之间有联系吗

• 批准号: 7173811
• 负责人: PAULA GRAMMAS
• 金额: $ 31.05万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7173811
• 关键词: Affect; Alleles; Alzheimer' s Disease; American; Apolipoprotein E; Apoptosis; Apoptotic; Atherosclerosis; Biological Assay; Blood Vessels; Brain; CCL2 gene; Cells; Cessation of life; Cognitive; Development; Diet; Disease; Endopeptidases; Endothelial Cells; Endothelin; Enzyme-Linked Immunosorbent Assay; Event; Functional disorder; Gelatinase A; Genotype; Human; Hyperhomocysteinemia; Hyperlipidemia; IL8 gene; Impairment; In Vitro; Inflammatory; Knock-out; Knockout Mice; Laboratories; Learning; Lesion; Link; Lipids; Matrix Metalloproteinases; Measures; Mediating; Memory; Memory impairment; Messenger RNA; N-terminal; Necrosis; Neurodegenerative Disorders; Neurons; Neurotoxins; Nitric Oxide; Northern Blotting; Oxidants; Oxidative Stress; Oxygen; Pathogenesis; Patients; Peptide Hydrolases; Performance; Play; Prevention; Protein Isoforms; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Rodent; Role; Stress; Testing; Therapeutic Intervention; Thrombin; Time; Transgenic Mice; Western Blotting; atherogenesis; cardiovascular risk factor; chemokine; cytokine; disease characteristic; hypercholesterolemia; in vivo; neuron loss; neurotoxic; neurotoxicity; novel; programs; protein expression; response to injury

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disease that affects over 4 million Americans. We are the first to demonstrate that brain blood vessels release neurotoxic proteins in Alzheimer's disease. However, the factors that cause this vessel dysfunction are not known. It is our hypothesis that risk factors involved in the pathogenesis of atherosclerosis are also causally linked to the development of vascular-mediated neuronal cell death in Alzheimer's disease. Our studies are timely and important as increasing evidence points to a link between atherosclerosis and Alzheimer's disease. Aim 1: To determine the effects of systemic oxidant stress or hyperlipidemia on vascular thrombin release, vascular-mediated neurotoxicity and on the cognitive performance of apoE transgenic mice. Brain blood vessels isolated from apoE knockout or transgenic mice expressing human E3 or E4 are used to assess the role of apoE isoforms on vascular expression of thrombin. Diet-induced hyperhomocystinemia and hyperlipidemia, are used to assess the role of oxidant stress and lipids, respectively, on vascular thrombin release and vascular-mediated neurotoxicity. Also, these transgenic mice are utilized to evaluate possible apoE isoform-specific effects of oxidant and lipid stress on impairments in learning and memory. Aim 2: To determine if risk factors involved in the pathogenesis of atherosclerosis are also causally linked to the development of vascular-mediated neuronal cell death in Alzheimer's disease. Brain microvessels are isolated from AD patients and non-demented patients and analyzed for levels and/or activity of thrombin and other possible neurotoxic proteins, including, matrix metalloproteinases (MMPs), inflammatory cytokines and chemokines, and endothelin-l. Protein levels are determined by ELISA and Western blots and Mrna levels assessed by Northern blots and RT-PCR. The role that apoE isoforms play in regulating these proteins is determined by comparing microvessels isolated from patients with different APOE genotypes. In vitro addition of oxygen species or lipid molecules to isolated brain microvessels is used to assess the effects of oxidative stress and lipids, respectively, on release of thrombin, MMPs, inflammatory proteins, and endothelin-l. Apoptosis and necrosis are measured in cultured neuronal cells exposed to these proteins. These results would, for the first time, identify a mechanistic cascade linking cardiovascular risk factors to vascular-mediated neuronal cell death in Alzheimer's disease and identify novel targets for therapeutic intervention.

描述（由申请人提供）：阿尔茨海默病（AD）是一种影响超过400万美国人的神经退行性疾病。我们是第一个证明在阿尔茨海默病中脑血管释放神经毒性蛋白质的人。然而，导致这种血管功能障碍的因素尚不清楚。我们的假设是，动脉粥样硬化发病的危险因素也与阿尔茨海默病中血管介导的神经元细胞死亡的发展有因果关系。我们的研究是及时和重要的，因为越来越多的证据表明动脉粥样硬化和阿尔茨海默病之间存在联系。目的1：确定全身氧化应激或高脂血症对载脂蛋白e转基因小鼠血管凝血酶释放、血管介导的神经毒性和认知能力的影响。从apoE敲除或表达人E3或E4的转基因小鼠中分离的脑血管被用来评估apoE亚型对血管凝血酶表达的作用。饮食诱导的高同型半胱氨酸血症和高脂血症分别用于评估氧化应激和脂质对血管凝血酶释放和血管介导的神经毒性的作用。此外，这些转基因小鼠被用来评估氧化应激和脂质应激对学习和记忆损伤可能的apoE亚型特异性影响。目的2：确定参与动脉粥样硬化发病机制的危险因素是否也与阿尔茨海默病中血管介导的神经元细胞死亡的发展有因果关系。从AD患者和非痴呆患者中分离出脑微血管，分析凝血酶和其他可能的神经毒性蛋白的水平和/或活性，包括基质金属蛋白酶（MMPs）、炎症细胞因子和趋化因子以及内皮素- 1。用ELISA和Western blots检测蛋白水平，用Northern blots和RT-PCR检测Mrna水平。通过比较不同apoE基因型患者分离的微血管，确定apoE亚型在调节这些蛋白中的作用。在离体脑微血管中添加氧或脂质分子分别用于评估氧化应激和脂质对凝血酶、MMPs、炎症蛋白和内皮素- 1释放的影响。在暴露于这些蛋白的培养神经元细胞中测量细胞凋亡和坏死。

项目成果

Brain endothelial cells synthesize neurotoxic thrombin in Alzheimer's disease.

• DOI: 10.2353/ajpath.2010.090406
• 发表时间: 2010-04
• 期刊: The American journal of pathology
• 作者: Xiangling Yin;Jill Wright;Trevor Wall;P. Grammas

RANTES release contributes to the protective action of PACAP38 against sodium nitroprusside in cortical neurons.

• DOI: 10.1016/j.npep.2009.05.002
• 发表时间: 2009-08
• 期刊: NEUROPEPTIDES
• 影响因子: 2.9
• 作者: Sanchez, Alma;Tripathy, Debjani;Grammas, Paula
• 通讯作者: Grammas, Paula

Endothelin-1 is elevated in Alzheimer's disease brain microvessels and is neuroprotective.

内皮素-1 在阿尔茨海默病脑部微血管中升高，具有神经保护作用。

• DOI: 10.3233/jad-2010-091486
• 发表时间: 2010
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Luo,Jinhua;Grammas,Paula
• 通讯作者: Grammas,Paula

Cyclin C and cyclin dependent kinases 1, 2 and 3 in thrombin-induced neuronal cell cycle progression and apoptosis.

• DOI: 10.1016/j.neulet.2008.12.018
• 发表时间: 2009-02-06
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Rao HV;Thirumangalakudi L;Grammas P
• 通讯作者: Grammas P

Angiogenic proteins are expressed by brain blood vessels in Alzheimer's disease.

血管生成蛋白由阿尔茨海默氏病的脑血管表达。

• DOI: 10.3233/jad-2006-10114
• 发表时间: 2006
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Thirumangalakudi,Lakshmi;Samany,PezhmanGhatreh;Owoso,Akinkunle;Wiskar,Brandt;Grammas,Paula
• 通讯作者: Grammas,Paula