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β蛋白(Aβ)的清除由神经胶质细胞促进，而Aβ清除受损与 阿尔茨海默病(AD)的发病机制。对神经胶质功能的非侵入性分析可以将这一知识转化为 改善健康结果--导致开发新的诊断工具和/或以胶质细胞为目标 治疗。与中枢神经系统(CNS)的其他部分相比，视网膜的结构简单。在 无血管的视网膜层，在那里唯一的神经元成分是光感受器，邻近的富含胶质细胞和胶质细胞- 游离层可以影响神经胶质细胞的健康。在这个项目中，大脑皮质无血管层对光的功能反应 视网膜将使用光学相干断层扫描(OCT)进行监测，这是一种非侵入性的、目前正在使用的技术 广泛的临床应用。视网膜富含胶质细胞层和无胶质细胞层的反应报告了局部水的变化 内容，这是胶质细胞介导的废物清除的基础。对于这个项目的第一个目标，我们将比较 AD患者、非阿尔茨海默病患者和健康老年人的功能OCT测量 相匹配的成年人。我们假设阿尔茨海默病患者的功能性OCT异常是疾病特有的，并存在于 疾病的早期阶段。阳性结果将验证一种新的低成本、非侵入性和诊断性的 AD的有用标记物。该项目的第二个目标是使用OCT非侵入性地测量视网膜神经胶质功能 在疾病的遗传小鼠模型中。缺乏水通道蛋白4蛋白的基因敲除小鼠神经胶质水受损 和垃圾清理。这些小鼠将与APP/PS1小鼠杂交，APP/PS1小鼠是基于Aβ的常见AD模型 生产过剩。这些小鼠的OCT功能异常可能是由于胶质水的限制引起的 运动，或由Aβ积聚，或AD的这些特征可能是协同的。体外培养神经胶质细胞的OCT研究 将阐明神经胶质细胞对OCT异常的影响。这一目标的积极发现将 验证OCT是第一个临床上可用的测量神经胶质功能的工具，并提供直接从细胞到鼠标到 神经退行性疾病中神经胶质功能评估的人类翻译方法。 我的职业目标是成为一名独立资助的研究AD及相关学科的内科科学家 痴呆症。这份有指导的职业发展建议建立在我作为研究员的临床经验基础上- 训练有素的痴呆症神经科医生，以及我在OCT对阿尔茨海默氏症患者以及(非OCT)的研究经验 啮齿动物视网膜的成像。加州大学戴维斯分校是建议培训的理想地点： 首席导师将指导我计划、组织和执行 研究所的NIA资助的阿尔茨海默病研究中心。导师和合作者组成的团队包括 由美国国立卫生研究院资助的经验丰富的视觉科学家，他们将提供先进的OCT技术和Müler glial方面的培训 细胞培养。此计划利用的其他加州大学戴维斯分校培训和分析资源包括： 视觉科学和神经胶质细胞生物学的高级课程，NIH资助的临床和翻译 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。