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)的病理特征和 死后人类和活体小鼠模型视网膜中的相关炎症。这些研究将 为第二代视网膜成像的发展提供基本的病理信息 方法对AD进行诊断、评估进展和监测治疗。该病的显著病理征象 脑内AD-淀粉样蛋白β-蛋白(A-β)斑块和神经原纤维缠结(NFT) 过度磷酸化的tau蛋白-也存在于视网膜中。视网膜表现出广泛的光谱 阿尔茨海默病患者的病理改变，包括神经纤维层变薄，血管改变和血管变性 视网膜神经节细胞。然而，直到最近，我们小组才在 阿尔茨海默病患者及早期患者的视网膜此外，我们的初步数据显示血管的表现。 Aβ聚集和周围的淀粉样蛋白沉积和视网膜炎症(如星形胶质细胞增生症、小胶质细胞增生症) NFT样结构，这是AD患者视网膜所特有的。为了可视化淀粉样蛋白病理，我们 开发了一种无创视网膜姜黄素成像方法，用于重复监测视网膜Aβ沉积 AD转基因小鼠活体模型的高分辨率和高特异性。初步研究还表明 使用光学成像设备追踪荧光标记的免疫细胞渗透到 活生生的老鼠视网膜。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 证明其有能力定量检测活体AD患者的视网膜Aβ沉积，但 AD的特异性和在疾病进展期间准确预测脑病理的能力表现为 这是一个巨大的挑战。在这项研究中，患有或不患有AD的受试者的视网膜和大脑样本配对 将评估大脑淀粉样血管病变和包括轻度认知障碍在内的对照组的 AD相关标志物和炎症标志物的空间分布；视网膜表现将与 相应的大脑。提出了以下研究目标：1)确定存在和 动脉和血管Aβ沉积、细胞内Aβ寡聚体的分布和疾病期间的相互作用 AD和MCI患者视网膜的进展，并与配对脑的视网膜病理进行比较 2)研究A-β相关的局部炎症、单核细胞浸润及其参与的临床意义。 AD和MCI患者视网膜摄取β，星形胶质细胞增生症和胶质细胞死亡并存； 无创性监测疾病期间视网膜Aβ沉积和单核细胞浸润的形成和清除 阿尔茨海默病活体小鼠模型的进展和对基于免疫的治疗的反应。这些研究的结果 这将显著增加人们对AD如何影响视网膜的理解。鉴于其对于直达的可访问性， 无创的高分辨率成像，靶向这个中枢神经系统组织可能提供一个关键的轴心来研究和 确定有助于AD风险预测、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.