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

摘要 这项提案的中心目标是探索阿尔茨海默病（AD）的病理特征， 在死后的人类和活的小鼠模型中的视网膜中的相关炎症。这些研究将 提供基本的病理信息，以允许开发第二代视网膜成像 诊断、评估进展和监测AD治疗的方法。典型的病理症状 脑中的AD-淀粉样β蛋白（Aβ）斑块和神经纤维缠结（NFT），包括 过度磷酸化的tau蛋白-也存在于视网膜中。视网膜呈现出广泛的 AD患者的病理学，包括神经纤维层变薄、血管变化和 视网膜神经节细胞然而，直到最近，我们的研究小组才发现AD特异性标志性Aβ沉积， AD患者和早期病例的视网膜。此外，我们的初步数据表明， Aβ聚集周围的淀粉样蛋白沉积和视网膜炎症（例如星形胶质细胞增生、小胶质细胞增生）， NFT样结构，其特异于AD患者的视网膜。为了可视化淀粉样蛋白病理学，我们 开发了一种非侵入性视网膜姜黄素成像方法，用于重复监测视网膜Aβ沉积， 高分辨率和特异性。初步研究还表明， 使用光学成像装置追踪荧光标记的免疫细胞浸润到 活的老鼠视网膜来自实施这种视网膜姜黄素成像技术的正在进行的临床试验的数据 证实了其定量检测活体AD患者视网膜Aβ沉积的能力，但建立了 AD的特异性和在疾病进展过程中忠实预测脑病理学的能力， 重大挑战。在这项研究中，视网膜和大脑的配对样本，从受试者与AD或没有 将评估脑淀粉样血管病和包括轻度认知障碍的对照的 AD相关和炎症标志物的空间分布;视网膜发现将与 相应的大脑。提出了以下研究目标：1）确定存在和 疾病期间Aβ沉积物、细胞内Aβ寡聚体和tau蛋白病变的分布 AD和MCI患者视网膜的进展，并将视网膜病理学与配对脑中的病理学进行比较。 2）研究Aβ相关的局部炎症、浸润的单核细胞及其参与 Aβ摄取，以及AD和MCI患者视网膜中星形胶质细胞增生和胶质细胞死亡的共同发生;以及3） 非侵入性监测疾病期间视网膜Aβ沉积物和单核细胞浸润的形成和清除 在AD的活小鼠模型中的进展和对基于免疫的治疗的响应。这些研究的结果 将显著增加对AD如何影响视网膜的理解。鉴于其可直接访问， 非侵入性高分辨率成像，针对这一中枢神经系统组织可以提供一个关键的轴调查， 鉴定有助于预测AD风险、诊断和监测的新生物标志物。

ABSTRACT The central goal of this proposal is to explore pathological hallmarks of Alzheimer’s disease (AD) and associated inflammation in retinas from post-mortem humans and in live mouse models. These studies will provide the basic pathological information to permit development of second-generation retinal imaging methods to diagnose, assess progression, and monitor treatments for AD. The hallmark pathological signs of AD in the brain – amyloid β-protein (Aβ) plaques and neurofibrillary tangles (NFTs) comprised of hyperphosphorylated tau protein – are also present in the retina. The retina exhibits a wide spectrum of pathologies in AD patients, including thinning of the nerve fiber layer, vascular changes, and degeneration of retinal ganglion cells. However, only recently were AD-specific hallmark Aβ deposits identified by our group in retinas of AD patients and early-stage cases. Further, our preliminary data indicate manifestation of vascular amyloid deposits and retinal inflammation (e.g. astrogliosis, microgliosis) surrounding Aβ aggregation and NFT-like structures, which are specific to the retinas of AD patients. To visualize amyloid pathology, we developed a noninvasive retinal curcumin imaging approach for repeated monitoring of retinal Aβ deposits with high resolution and specificity in living transgenic mouse models of AD. Preliminary studies also demonstrate the feasibility of using an optical imaging device to track infiltration of fluorescently labeled immune cells into the live mouse retina. Data from ongoing clinical trials implementing this retinal curcumin imaging technology demonstrate its capacity to quantitatively detect retinal Aβ deposits in living AD patients, but establishing specificity for AD and the ability to faithfully predict cerebral pathology during disease progression presents a significant challenge. In this study, paired samples of retina and brain from subjects with AD with or without cerebral amyloid angiopathy and from controls including mild cognitive impairment will be assessed for the spatial distribution of AD-related and inflammatory markers; retinal findings will be correlated with those in the corresponding brain. The following research objectives are proposed: 1) to determine the existence and distribution of abluminal and vascular Aβ deposits, intracellular Aβ oligomers, and tauopathy during disease progression in the retina of AD and MCI patients, and to compare retinal pathology to that in the paired brain sample; 2) to investigate the Aβ-associated local inflammation, infiltrating monocytes and their involvement in Aβ uptake, and co-occurrence of astrogliosis and glial cell death in retinas of AD and MCI patients; and 3) to noninvasively monitor formation and clearance of retinal Aβ deposits and monocytes infiltration during disease progression and in response to immune-based therapy in live mouse models of AD. Results from these studies stand to markedly increase the understanding of how AD affects the retina. Given its accessibility for direct, noninvasive high-resolution imaging, targeting this CNS tissue may provide a key axis to investigate and identify new biomarkers that facilitate prediction of risk, diagnosis, and monitoring of AD.