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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' 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' 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

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.

项目摘要 /摘要 淀粉样蛋白β（Aβ）的清除是由神经胶质细胞制备的，并且Aβ清除受损与 阿尔茨海默氏病的发病机理（AD）。对神经胶质功能的非侵入性评估可以转化这一知识 改善健康成果 - 导致开发新的诊断工具和/或靶向神经胶质的工具 疗法。与中枢神经系统（CNS）的其他部位相比，视网膜在结构上很简单。之内 血管层是视网膜，其中唯一的神经元元素是感光体，邻近的胶质和胶质 自由层可以告知神经胶质健康。在这个项目中，功能响应在那些血管层中的光响应 视网膜将通过光学相干断层扫描（OCT）进行监测，这是无创的，目前 宽度临床使用。视网膜含量丰富和无胶质层的响应报道了水中的局部变化 内容，是胶质介导的废物清除的基础。对于该项目的第一个目的，我们将比较 AD患者，非阿尔茨海默氏症患者的功能性OCT测量以及健康的年龄 - 匹配的成年人。我们假设AD的功能性OCT异常是特异性的，并且存在于 疾病的早​​期阶段。积极的结果将验证新的低成本，无创和诊断 AD的有用标记。该项目的第二个目的将使用OCT来非侵入性测量残留神经胶质功能 在疾病的遗传小鼠模型中。缺乏水通道蛋白4蛋白的敲除小鼠的神经胶质水受损 和浪费清除。这些小鼠将与App/PS1小鼠交叉，APP/PS1小鼠是基于Aβ的AD的常见模型 生产过剩。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，或通过Aβ积累，或AD的这些特征可能是协同作用的。培养的神经胶质细胞的体外OCT 这些小鼠将阐明对OCT异常的神经胶质贡献。这个目标的积极发现将 验证OCT是第一个测量神经胶质功能的临床上可用工具，并提供直接的细胞对小鼠至小鼠 人类翻译方法用于评估神经退行性疾病中的神经胶质功能。 我的职业目标是成为由独立资助的身体科学家学习广告和相关的 痴呆症。这项修补了职业发展建议是基于我作为奖学金的临床经验的基础 受过训练的痴呆症神经科医生以及我在阿尔茨海默氏症患者的OCT和（非OCT）的研究经验 啮齿动物视网膜的成像。加利福尼亚大学 - 戴维斯是拟议培训的理想场所： 主要导师将指导我在计划，组织和执行资助的人类研究 机构NIA资助的阿尔茨海默氏病研究中心。导师和合作者团队包括 经验丰富的NIH资助的视觉科学家将提供高级OCT技术和MüllerGlial的培训 细胞培养。该提案利用的其他UC Davis培训和分析资源包括研究生 NIH资助的临床和翻译的视觉科学与生物学的水平课程 科学中心和NIH资助的突变小鼠区域资源中心。