Illuminating Glial Dysfunction in Alzheimer’s Disease with Optical Coherence Tomography

利用光学相干断层扫描揭示阿尔茨海默病中的神经胶质功能障碍

基本信息

批准号：
10571184
负责人：
David Philip Bissig
金额：
$ 16.4万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10571184
关键词：
APP-PS1 Abeta clearance Adult Age Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amino Acids Amyloid Amyloid beta-Protein Anatomy Antibodies Biological Assay Biology Blood Vessels Brain California Cell Culture Techniques Cells Center for Translational Science Activities Central Nervous System Cerebrospinal Fluid Clinic Clinical Clinical Sciences Clinical Trials Cognitive Dementia Detection Development Diagnosis Diagnostic tests Disease Disease model Elements Fellowship Functional disorder Funding Genetic Genetic Polymorphism Goals Health Human Image Impaired cognition Impairment In Vitro Institution Intercellular Fluid Intervention Knockout Mice Knowledge Light Link Location Measurement Measures Mediating Memory impairment Mentors Methods Modeling Monitor Muller&apos s cell Mus Mutant Strains Mice Neurodegenerative Disorders Neuroglia Neurologist Neurology Neurons Ocular Pathology Optical Coherence Tomography Osmosis Outcome Pathogenesis Pathologic Pathway interactions Patients Persons Photoreceptors Physicians Physiological Physiology Positron-Emission Tomography Production Protein Isoforms Proteins Reporting Research Research Personnel Resources Retina Rodent Role Scientist Senile Plaques Signal Transduction Techniques Technology Testing Training Translating United States National Institutes of Health Universities Vision Water Water Movements abeta accumulation age related aquaporin 4 biomarker development career career development cost diagnostic tool experience fluid flow glymphatic dysfunction glymphatic system imaging modality improved interstitial knockout animal microscopic imaging mild cognitive impairment monomer mouse model next generation non-invasive imaging nonalzheimer dementia novel novel diagnostics novel marker recruit response retinal imaging skills targeted treatment tool translation assay translation to humans translational approach translational neuroscience vision science wasting water channel

项目摘要

PROJECT SUMMARY / ABSTRACT Clearance of amyloid beta (Aβ) is facilitated by glial cells, and impaired Aβ clearance is implicated in the pathogenesis of Alzheimer’s disease (AD). A non-invasive assay of glial function could translate this knowledge into improved health outcomes – leading to the development of new diagnostic tools and/or glia-targeted therapies. Compared to other parts of the central nervous system (CNS), the retina is structurally simple. Within the avascular layers the retina, where the only neuronal elements are photoreceptors, adjacent glia-rich and glia- free layers can inform on glial health. In this project, functional responses to light in those avascular layers of the retina will be monitored with optical coherence tomography (OCT), which is non-invasive and in current widespread clinical use. Responses in the glia-rich and glia-free layers of the retina report on local shifts in water content, which are foundational to glia-mediated waste clearance. For the first Aim of this project, we will compare functional OCT measurements in patients with AD, patients with non-Alzheimer’s dementia, and healthy age- matched adults. We hypothesize that the functional OCT abnormality in AD is disease-specific and is present at early stages of the disease. Positive results would validate a new low-cost, non-invasive, and diagnostically useful marker of AD. The second Aim of this project will use OCT to non-invasively measure retinal glial function in genetic mouse models of disease. Knockout mice lacking the aquaporin 4 protein have impaired glial water and waste clearance. Those mice will be crossed with APP/PS1 mice, a common model of AD based on Aβ overproduction. Functional OCT abnormalities in these mice may be caused by limitations in glial water movement, or by Aβ accumulation, or these features of AD may be synergistic. In vitro OCT of glial cells cultured from those mice will clarify the glial contribution to OCT abnormalities. Positive findings from this Aim would validate OCT as the first clinically-available tool to measure glial function, and provide a direct cell-to-mouse-to- human translational approach for the assessment of glial function in neurodegenerative disease. My career goal is to become an independently-funded physician-scientist studying AD and related dementias. This mentored career development proposal builds upon my clinical experience as a fellowship- trained dementia neurologist, and my research experience in OCT in Alzheimer’s patients as well as (non-OCT) imaging of the rodent retina. The University of California – Davis is the ideal location for the proposed training: The primary mentor will guide me in planning, organizing, and executing funded human research at the institution’s NIA-funded Alzheimer’s Disease Research Center. The team of mentors and collaborators includes experienced NIH-funded vision scientists who will provide training in advanced OCT techniques and Müller glial cell culture. Additional UC Davis training and analytic resources leveraged by this proposal include graduate- level coursework in vision science and the biology of neuroglia, the NIH-funded Clinical and Translational Science Center, and the NIH-funded Mutant Mouse Regional Resource Center.

项目概要/摘要神经胶质细胞促进β淀粉样蛋白（Aβ）的清除，Aβ清除受损与阿尔茨海默氏病（AD）的发病机制可以转化为神经胶质功能的非侵入性检测知识。改善健康结果——导致新诊断工具和/或针对神经胶质细胞的开发与中枢神经系统（CNS）的其他部分相比，视网膜的结构很简单。视网膜的无血管层，其中唯一的神经元元件是光感受器，邻近富含神经胶质细胞和神经胶质细胞自由层可以了解神经胶质的健康状况，在这个项目中，这些无血管层对光的功能反应。视网膜将通过光学相干断层扫描（OCT）进行监测，这是非侵入性的，并且是目前最先进的技术。视网膜富含胶质细胞和无胶质细胞层的反应报告了水的局部变化。内容，这是神经胶质介导的废物清除的基础，对于该项目的第一个目标，我们将进行比较。 AD 患者、非阿尔茨海默氏痴呆患者和健康年龄患者的功能性 OCT 测量我们认为 AD 中的功能性 OCT 异常是疾病特异性的，并且存在于 AD 中。疾病早期阶段的积极结果将验证一种新的低成本、非侵入性的诊断方法。该项目的第二个目标是使用 OCT 无创测量视网膜胶质细胞功能。在疾病的遗传小鼠模型中，缺乏水通道蛋白 4 蛋白的基因敲除小鼠的胶质水受损。这些小鼠将与 APP/PS1 小鼠（一种基于 Aβ 的常见 AD 模型）杂交。这些小鼠的功能性 OCT 异常可能是由于神经胶质水的限制引起的。运动或 Aβ 积累，或者 AD 的这些特征可能与培养的神经胶质细胞的体外 OCT 具有协同作用。来自这些小鼠的结果将阐明神经胶质细胞对 OCT 异常的影响。验证 OCT 作为第一个临床可用的测量神经胶质功能的工具，并提供直接的细胞到小鼠到用于评估神经退行性疾病中神经胶质功能的人类转化方法。我的职业目标是成为一名独立资助的医师科学家，研究 AD 及相关领域这个指导性的职业发展建议建立在我作为研究员的临床经验之上。训练有素的痴呆症神经科医生，以及我在阿尔茨海默氏症患者的 OCT 以及（非 OCT）方面的研究经验啮齿动物视网膜成像。加州大学戴维斯分校是拟议培训的理想地点：主要导师将指导我规划、组织和执行资助的人类研究该机构由 NIA 资助的阿尔茨海默病研究中心的导师和合作者包括。 NIH 资助的经验丰富的视觉科学家将提供先进 OCT 技术和穆勒胶质细胞的培训该提案利用的额外加州大学戴维斯分校培训和分析资源包括研究生- 视觉科学和神经胶质细胞生物学的水平课程，美国国立卫生研究院资助的临床和转化科学中心和美国国立卫生研究院资助的突变小鼠区域资源中心。