Roles of Tau Oligomers in Alzheimer's Vasculopathy

Tau 寡聚体在阿尔茨海默病血管病变中的作用

基本信息

批准号：
10405024
负责人：
JAMES C LEE
金额：
$ 38.89万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10405024
关键词：
3xTg-AD mouse Actins Adhesions Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease patient Amyloid beta-Protein Angiography Atomic Force Microscopy Automobile Driving Biochemical Biophotonics Blood - brain barrier anatomy Blood Vessels Brain Caliber Cell Adhesion Molecules Cell physiology Cell surface Cells Characteristics Clinical Cytoplasm Cytoskeleton Cytosolic Phospholipase A2 Defect Deposition E-Selectin Extracellular Fluid Fluorescence Microscopy Ganglionic Layer Gender Human ICAM2 gene Infiltration Inflammation Inflammatory Intercellular adhesion molecule 1 Lead Leukocytes Measures Mechanics Mediating Membrane Methods Mus NADPH Oxidase Nerve Degeneration Neurofibrillary Tangles Neurons Optical Coherence Tomography Oxidants Oxidative Stress P-Selectin Pathology Pathway interactions Phosphorylation Physiological Probability Reporting Research Resolution Retina Role Selectins Side Study models Testing Tg2576 Therapeutic Thick Thinness Transgenic Mice Up-Regulation Vascular Cell Adhesion Molecule-1 Vascular Diseases amyloid pathology brain endothelial cell density early detection biomarkers extracellular indexing innovation insight interdisciplinary approach mechanical force migration monocyte mouse model neurovascular oAβ p65 peripheral blood polymerization protein expression response retina blood vessel structure statistics tau Proteins tau aggregation

项目摘要

Extracellular oligomeric tau (o-tau) and vascular deposition of o-tau has been observed in brains of Alzheimer's disease (AD) patients. In this project, we propose to examine how the direct interactions of o-tau with the basolateral side of human brain microvascular endothelial cells (HBMECs) impact their function, including oxidative stress, inflammation, adhesion molecule expression, membrane tether adhesion, and transendothelial migration of monocytes through activations of NADPH oxidase, cytosolic phospholipase A2 and NFκB. As retina is a part of the brain, we also employ the non-invasive optical coherence tomography (OCT) and OCT angiography (OCTA) (i.e. OCT/OCTA) to study microvascular characteristics and neurodegeneration, as quantified by the ganglion layer thickness (GLT), and their relations to oligomeric amyloid-β (oAβ), and o-tau contents in retinas of Tg AD mouse models for studying the influences of human tau and amyloid pathology including APPswe/PSEN1dE9 and 3xTg AD mice. This project will fill the research gap between extracellular o-tau and neurovascular abnormalities in AD by providing information regarding adhesion mechanical responses to o-tau in HBMECs, and changes in retinal vessel network characteristics and GLT in relations to Aβ and o-tau, and ultimately provide insights into therapeutic strategies for AD treatment by regulating tau's effects.

在阿尔茨海默病患者的大脑中观察到细胞外寡聚 tau (o-tau) 和 o-tau 的血管沉积在这个项目中，我们建议研究 o-tau 与 AD 患者的直接相互作用。人脑微血管内皮细胞 (HBMEC) 的基底外侧影响其功能，包括氧化应激、炎症、粘附分子表达、膜系绳粘附和跨内皮细胞通过 NADPH 氧化酶、胞质磷脂酶 A2 的激活实现单核细胞的迁移由于视网膜是大脑的一部分，因此我们还采用了非侵入性光学相干断层扫描。 (OCT) 和 OCT 血管造影 (OCTA)（即 OCT/OCTA），用于研究微血管特征和神经变性，通过神经节层厚度（GLT）量化，及其与寡聚体的关系 Tg AD 小鼠模型视网膜中淀粉样蛋白-β (oAβ) 和 o-tau 含量，用于研究人类 tau 蛋白的影响以及淀粉样蛋白病理学，包括 APPswe/PSEN1dE9 和 3xTg AD 小鼠，该项目将填补研究空白。通过提供有关粘附的信息来研究 AD 细胞外 o-tau 与神经血管异常之间的关系 HBMEC 对 o-tau 的机械反应，以及视网膜血管网络特征和 GLT 的变化与 Aβ 和 o-tau 的关系，并最终为 AD 治疗策略提供见解调节 tau 蛋白的作用。