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Near infrared fluorescence imaging of reactive oxygen species in Alzheimer's disease

阿尔茨海默病活性氧的近红外荧光成像

基本信息

批准号：
10347304
负责人：
Chongzhao Ran
金额：
$ 41.99万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10347304
关键词：
3xTg-AD mouse APP-PS1 Age Age-Months Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Alzheimer&apos s disease therapy Amyloid beta-Protein Animal Model Antibodies Antioxidants Brain Brain imaging Cells Chemistry Clinical Trials Cognition Consequentialism Curcumin Data Disease Progression Esters Excision Fluorescence Hydrogen Peroxide Image Immunotherapy In Vitro Inflammation Inflammatory Response Lead Microglia Monitor Mus Near-infrared optical imaging Neurodegenerative Disorders Oxalates Oxidative Stress Patient imaging Peripheral Pharmaceutical Preparations Play Positron-Emission Tomography Production Reaction Reactive Oxygen Species Regimen Reporting Role Senile Plaques Series Testing Time Tissues Transgenic Mice Validation abeta accumulation age related blood-brain barrier penetration design drug development imaging agent imaging modality imaging probe improved in vitro testing in vivo in vivo imaging non-invasive imaging patient subsets pre-clinical quantum response scaffold tau Proteins

项目摘要

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder, whose progression is closely associated with oxidative stress. It has long been speculated that the reactive oxygen species (ROS) level in AD brains is much higher than that in healthy brains. However, evidence from living beings is rare. Studies suggest that a vicious cycle revolves around amyloid beta (Aβ) and Tau production/aggregation, microglia responses, inflammatory responses, and ROS production. In this cycle, ROS species play a central role. Many clinical trials indicate that drugs can effectively engage with Aβ and remove Aβ plaques, but none of the trials have shown clear benefits of improving cognition. Nonetheless, it is not clear whether the removal of Aβs can lead to the changes of ROS levels in brains during the therapy. To answer these fundamental and critically important questions, in this application, we propose to use Near Infrared Fluorescence (NIRF) imaging to monitor ROS changes in living AD brains during disease progression and therapy in preclinical animal models. Inspired by the chemistry of glow sticks, we have designed a NIRF probe, termed CRANAD-61 for detecting ROS. In glow sticks, oxalate esters react with H2O2 to produce chemiluminescence. In CRANAD-61, an oxalate moiety was utilized to react with ROS and to consequentially produce wavelength shifting. Our in vitro data showed that CRANAD-61 was highly sensitive and rapidly responsive to various ROS. Upon reacting with ROS, its excitation and emission wavelengths significantly shifted, and this shifting could be harnessed for dual-wavelength imaging. We showed that, for the first time, age-related increases in ROS levels in AD brains could be monitored with our NIRF imaging method. In this application, we propose to further structurally optimize CRANAD-61 by extending excitation/emission to make them suitable for dual-wavelength imaging in the NIR window. We will then use the optimized probe to monitor the changes of ROS during the progression of AD in transgenic mice, and during therapy with an Aβ antibody. We will investigate whether Aβ-lowering treatment can lead to a decrease of ROS, and whether a combination of Aβ-reduction and anti-oxidant or anti-inflammation therapies should be considered for AD treatment. The answers from our studies will improve and guide the paradigm of AD therapy regimens.

阿尔茨海默病（Alzheimer's disease，AD）是一种不可逆的神经退行性疾病，其进展与阿尔茨海默病的发病机制密切相关。与氧化应激有关。长期以来，人们一直推测，体内的活性氧（ROS）水平 AD患者的脑组织比健康人高得多。然而，来自生物的证据是罕见的。研究表明围绕淀粉样蛋白β（Aβ）和Tau产生/聚集、小胶质细胞反应，炎症反应和ROS产生。在这个循环中，ROS物种起着核心作用。许多临床试验表明，药物可以有效地与Aβ结合并清除Aβ斑块，但没有一项试验已经显示出明显的改善认知的益处。尽管如此，目前尚不清楚Aβs的去除是否可以导致治疗过程中脑内ROS水平的变化。为了回答这些基本的和批判性的问题，重要问题，在此应用中，我们建议使用近红外荧光（NIRF）成像来在临床前动物模型中监测疾病进展和治疗期间活体AD脑中的ROS变化。受荧光棒化学性质的启发，我们设计了一种NIRF探针，称为CRANAD-61，用于检测罗斯在荧光棒中，草酸酯与H2 O2反应产生化学发光。在CRANAD-61中，部分用于与ROS反应并因此产生波长偏移。我们的体外数据结果表明，CRANAD-61对各种ROS具有高度敏感性和快速响应性。在与 ROS的激发和发射波长发生了显著的变化，这种变化可以用于双波长成像我们第一次发现，在AD患者的大脑中，可以用我们的近红外成像方法来监测。在该应用中，我们建议通过将激发/发射扩展到使其适合于NIR窗口中的双波长成像。然后，我们将使用优化的探针，监测转基因小鼠AD进展期间和Aβ治疗期间ROS的变化抗体的我们将研究降低Aβ的治疗是否可以导致ROS的减少，以及是否可以通过降低A β的水平来降低ROS。对于AD，应考虑降低Aβ和抗氧化或抗炎治疗的组合治疗我们的研究将改善和指导AD治疗方案的范例。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Epitope alteration by small molecules and applications in drug discovery.

DOI：
10.1039/d2sc02819k
发表时间：
2022-07-13
期刊：
Chemical science
影响因子：
8.4
作者：
通讯作者：

In vivo three-dimensional brain imaging with chemiluminescence probes in Alzheimer's disease models.

DOI：
10.1073/pnas.2310131120
发表时间：
2023-12
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Jing Zhang;C. Wickizer;Weihua Ding;Richard Van;Liuyue Yang;Biyue Zhu;Jun Yang;Yanli Wang;Yongle Wang;Yulong Xu;Can Zhang;Shiqian Shen;Changning Wang;Yihan Shao;Chongzhao Ran
通讯作者：
Jing Zhang;C. Wickizer;Weihua Ding;Richard Van;Liuyue Yang;Biyue Zhu;Jun Yang;Yanli Wang;Yongle Wang;Yulong Xu;Can Zhang;Shiqian Shen;Changning Wang;Yihan Shao;Chongzhao Ran

The Application of Bio-orthogonality for In Vivo Animal Imaging.

生物实行性在体内动物成像中的应用。