Oxidative stress-induced vascular pathology and dysfunction in Alzheimer’s disease

阿尔茨海默病中氧化应激诱导的血管病理学和功能障碍

基本信息

批准号：
10523897
负责人：
Pradoldej Sompol
金额：
$ 42.08万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10523897
关键词：
3-nitrotyrosine Age Aging Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease therapeutic Amyloid beta-Protein Animal Model Animals Astrocytes Autopsy Award Basement membrane Biological Markers Blood Vessels Blood capillaries Blood flow Brain Cell Adhesion Cerebrovascular Disorders Cerebrum Cognition Complex Confocal Microscopy Contralateral Dementia Deposition Development Disease Progression Dyes Electrophysiology (science)Endothelial Cells Extracellular Matrix Proteins Extravasation Fibronectins Frequencies Functional disorder Future Hemorrhage Hippocampus (Brain)Human Hyperemia Image Image Analysis Imaging Techniques Impaired cognition Impairment Individual Infarction Knowledge Label Laser Speckle Imaging Lead Link Long-Term Potentiation Measures Mediating Memory Modeling Monitor Mus Neuronal Dysfunction Nitrogen Oxidative Stress Oxygen Pathologic Pathology Peripheral Peroxonitrite Physiology Pre-Clinical Model Process Proteins Protocols documentation Research Project Grants Resolution Resources Rodent Role Rose Bengal Route Saline Sampling Slice Specimen Stimulus Structure Synapses Synaptic plasticity Techniques Testing Three-Dimensional Image Thrombosis Time Tissue Harvesting Tissues Tyrosine Validation Vascular Diseases Vibrissae Work amyloid pathology arteriole barrel cortex brain tissue cerebrovascular cerebrovascular pathology cognitive function comorbidity experimental study imaging approach insight intravital imaging macromolecule microscopic imaging microvascular pathology mouse model multiphoton imaging multiphoton microscopy neocortical neurovascular neurovascular coupling non-demented novel oxidative damage photoactivation pre-clinical synaptic function thrombotic time use treatment strategy two-photon vascular cognitive impairment and dementia vascular injury vector

项目摘要

PROJECT SUMMARY/ ABSTRACT Vascular contributions to cognitive impairment and dementia (VCID) is highly comorbid with Alzheimer's disease (AD) where it exacerbates and hastens functional deficits. Mechanistic studies of vascular pathology formation and its effects on brain function, especially in AD, is limited. Developing translational imaging for application to mixed pathology models is necessary to understand the complex pathophysiological processes that link VCID and AD. Recently, we modified and optimized the oxidative stress-induced photothrombosis protocol (I.e. photoactivation of IV-injected Rose Bengal dye) for targeting individual capillaries in rodents. The major advantage of this novel vascular oxidative stress model is that vessel stalls, occlusion, and microhemorrhage can be followed in single capillaries in living mice, in real time, using multiphoton imaging. In this R21, we aim to apply this technique to 5xFAD mice to generate and characterize a novel AD/VCID mouse model en route to determining fibronectin— a matrix protein that supports vascular structure and integrity—as an indicator for the oxidative stress that arises from both cerebrovascular disease and AD. Our ongoing work on postmortem human brain specimens has revealed that astrocyte-derived fibronectin strongly colocalizes with the oxidative stress marker, nitrotyrosine (NT) especially around cerebrovessels and Aβ deposits. Photothrombosis of small cerebral arterioles revealed accumulation of fibronectin/NT colocalization at intravascular and nearby perivascular regions, similar to what we observe in human AD brain tissue. Here, we propose to use cutting edge physiology approaches combined with human postmortem brain specimens from our world class brain bank at the Sanders-Brown Center on Aging, to test the hypothesis that oxidative stress—indicated by NT incorporation into fibronectin— exacerbates cerebrovascular and synaptic dysfunction in the context of AD. In Aim 1, we will determine the effect of microvascular oxidative stress on neurovascular function in WT and 5xFAD mice. Multiphoton imaging techniques will be used to apply and to observe, in real-time, the development of microvascular pathologies including blood vessel stalls, vessel occlusion (infarct), and microhemorrhage as well as their effects on neurovascular coupling. Mouse brain tissues and postmortem samples from humans with confirmed vascular pathology and AD pathology will also be used to assess fibronectin/NT interactions with blood vessels, and to cross-validate our novel photothrombotic mouse model of mixed AD/VCID pathology. In Aim2, we will test the hypothesis that oxidative stress-induced microvascular pathology in 5xFAD mice leads to the global exacerbation of cognition and synaptic function in the context of AD-like pathology. The proposed studies will fill a critical knowledge gap surrounding the convergence of pathologic sequelae in cerebrovascular disease and AD. Moreover, establishment of a novel mouse model for mixed AD/VCID pathology will help inform new strategies for treating individuals with both AD and vascular pathology.

项目概要/摘要血管对认知障碍和痴呆 (VCID) 的影响与阿尔茨海默病高度共存疾病（AD），其恶化并加速血管病理学的机制研究。其形成及其对大脑功能的影响，特别是在 AD 中，开发转化成像是有限的。应用混合病理学模型对于理解复杂的病理生理过程是必要的最近，我们修改并优化了氧化应激诱导的光血栓形成。用于靶向啮齿类动物个体毛细血管的方案（即静脉注射孟加拉玫瑰染料的光激活）。这种新型血管氧化应激模型的主要优点是血管失速、闭塞和使用多光子成像可以实时追踪活体小鼠单个毛细血管的微出血。对于 R21，我们的目标是将该技术应用于 5xFAD 小鼠，以生成并表征新型 AD/VCID 小鼠确定纤连蛋白（一种支持血管结构和完整性的基质蛋白）的模型我们正在进行的工作是脑血管疾病和 AD 引起的氧化应激的指标。对死后人脑标本的研究表明，星形胶质细胞衍生的纤连蛋白强烈共定位氧化应激标记物硝基酪氨酸 (NT) 尤其是在脑血管和 Aβ 沉积物周围。大脑小动脉的光血栓形成揭示了纤连蛋白/NT共定位的积累血管内和附近的血管周围区域，类似于我们在人类 AD 脑组织中观察到的情况。建议使用尖端生理学方法与人类死后大脑标本相结合我们位于桑德斯-布朗衰老中心的世界级脑库，旨在检验氧化作用的假设 NT 掺入纤连蛋白表明应激会加剧脑血管和突触在目标 1 中，我们将确定微血管氧化应激对 AD 的影响。 WT 和 5xFAD 小鼠的神经血管功能将被用于应用和研究。实时观察微血管病变的发展，包括血管失速、血管闭塞（梗塞）和微出血及其对小鼠大脑神经血管耦合的影响。来自已确认血管病理学和 AD 病理学的人类组织和死后样本也将用于评估纤连蛋白/NT 与血管的相互作用，并交叉验证我们的新颖 AD/VCID 混合病理的光血栓小鼠模型在 Aim2 中，我们将检验氧化的假设。 5xFAD 小鼠中应激诱导的微血管病理导致认知和认知能力的全面恶化拟议的研究将填补 AD 样病理学中的关键知识空白。围绕脑血管疾病和 AD 病理后遗症的融合。建立 AD/VCID 混合病理学的新型小鼠模型将有助于提供新的治疗策略同时患有 AD 和血管病理学的个体。