Alzheimer's Disease Hallmark Pathology and Associated Inflammation in the Retina

项目总结/摘要 这项建议的中心目标是研究视网膜小胶质细胞表型，因为它们与新形式的视网膜神经胶质细胞相关。 研究阿尔茨海默病（AD）视网膜中的tau蛋白病和淀粉样变性，并确定它们与视网膜病变的关系。 神经血管单位改变和突触丧失以及脑中的疾病状态。我们将分析 尸检视网膜和配对的大脑，来自神经病理学特征良好的轻度 认知障碍（MCI）、AD痴呆和正常认知（NC），以及保持 尽管患有AD病理，但认知正常。AD病理标志物-淀粉样β蛋白（Aβ）的证据 由过度磷酸化的（p）tau蛋白组成的斑块和神经纤维缠结（NFT）-延伸至 视网膜和大脑病理学之间存在相似之处。最近，我们发现早期 血管血小板衍生生长因子受体β（vPDGFRβ）和周细胞丢失的进行性缺陷 在MCI和AD患者的死后视网膜中。视网膜vPDGFRβ与视网膜vAβ40和vAβ42相关 负荷、脑淀粉样血管病严重程度和认知评分。在旧的APPSWE/PS1ΔE9转基因（AD+）模型中 在小鼠中，我们揭示了视网膜和脑病理学与免疫治疗反应之间的相似性。我们还发现 在年轻和成年AD+小鼠中，视网膜毛细血管和vPDGFRβ损失与血管Aβ沉积有关， 与改变的内血视网膜屏障（iBRB）紧密连接和BRB渗漏相关。在人类中，我们 初步数据表明存在Aβ寡聚体、不同的pTau和瓜氨酸化Tau形式、小神经胶质增生， 星形胶质细胞增生，以及MCI和AD患者视网膜中的细胞特异性和突触损失，这些与 脑Aβ、tau蛋白病、神经变性和认知状态。蛋白质组学分析鉴定了新的分子 在视网膜中的AD的签名，与皮质区域的最大重叠。AD中最重要的途径 视网膜与炎症、代谢/线粒体损伤和神经变性有关，特别是在 光感受器我们的初步研究结果还表明，神经变性相关的小胶质细胞（MGnD） AD视网膜中的标记物。在这个项目中，AD标志性病理的视网膜空间分布和相关的 将确定炎症、神经血管和神经退行性标志物，并将其与相应的 大脑病理学和认知。具体目标包括：1）表征炎症过程， MCI和AD患者对比NC和AD患者视网膜中与新型tau蛋白病和淀粉样变性相关的MGnD 2）研究突触和细胞类型的脆弱性，并确定它们与tau蛋白病的关系， 3）确定iBRB损伤是否与血管内皮细胞损伤相关; 淀粉样变性、tau蛋白病和炎症。计算数据 科学工具将用于整合多组学数据集。结果将提供更深入的了解 视网膜和脑AD的分子和细胞炎症、血管和神经变性机制 病理学，为新的治疗靶点和下一代视网膜成像诊断策略铺平了道路。

PROJECT SUMMARY/ABSTRACT The central goal of this proposal is to investigate retinal microglial phenotypes as they relate to novel forms of tauopathy and amyloidosis in the Alzheimer's Disease (AD) retina and to determine their connections to retinal neurovascular unit alterations and synaptic loss as well as disease status in the brain. We will analyze postmortem retinas and paired brains from neuropathologically well-characterized patient donors with mild cognitive impairment (MCI), AD dementia, and normal cognition (NC), and resilient subjects who remained cognitively normal despite having AD pathology. Evidence of AD pathological hallmarks—amyloid β-protein (Aβ) plaques and neurofibrillary tangles (NFTs) composed of hyper-phosphorylated (p)tau protein—extending to the accessible retina is mounting, with parallels between retinal and brain pathology. Recently, we identified early and progressive deficiency in vascular platelet–derived growth factor receptor beta (vPDGFRβ) and pericyte loss in postmortem retinas of MCI and AD patients. Retinal vPDGFRβ was associated with retinal vAβ40 and vAβ42 loads, cerebral amyloid angiopathy severity, and cognitive scores. In old APPSWE/PS1ΔE9-transgenic (AD+) model mice, we revealed similarities between retinal and brain pathology and immunotherapy response. We also found that retinal capillary and vPDGFRβ losses link to vascular Aβ deposits in young and adult AD+ mice, and are associated with altered inner blood-retina barrier (iBRB) tight junctions and BRB leakage. In humans, our preliminary data suggest the existence of Aβ oligomers, diverse pTau and citrullinated Tau forms, microgliosis, astrogliosis, and cell-specific and synaptic losses in the retinas of MCI and AD patients, which correlate with brain Aβ, tauopathy, neurodegeneration, and cognitive status. Proteomics analysis identified novel molecular signatures of AD in the retina, with the largest overlap with a cortical region. Most significant pathways in the AD retina are related to inflammation, metabolic/mitochondrial damage, and neurodegeneration, especially in photoreceptors. Our initial findings also indicate increased neurodegeneration-associated microglia (MGnD) markers in the AD retina. In this project, retinal spatial distribution of AD hallmark pathology and associated inflammatory, neurovascular, and neurodegenerative markers will be determined and correlated with respective brain pathology and cognition. The specific objectives include 1) Characterize inflammatory processes and MGnD in relation to novel forms of tauopathy and amyloidosis in retinas of MCI and AD patients versus NC and resilient subjects; 2) Investigate synaptic and cell-type vulnerabilities and define their relations to tauopathy and microglial phenotypes in the same human cohort; and 3) Determine if iBRB damage is associated with vascular amyloidosis, tauopathy and inflammation in the human AD retina and in murine models. Computational data science tools will be applied to integrate the multi-omics data sets. Results will offer a deeper understanding of the molecular and cellular inflammatory, vascular, and neurodegeneration mechanisms of retinal and brain AD pathology, paving the path for novel therapeutic targets and next-generation retinal imaging diagnostic strategies.