Disease Mechanisms at the Intersection of Glaucoma and Alzheimer's Disease

项目概要/摘要： 阿尔茨海默病（Alzheimer's disease，AD）和青光眼是两种最常见的与年龄相关的神经退行性疾病 全世界公认。在全球范围内，AD是痴呆症最普遍的原因，也是死亡的主要原因， 而青光眼是不可逆失明的主要原因。在青光眼中，特征性视神经病变是 与进行性视野缺陷相关。目前这两种疾病都没有治愈方法，尽管治疗方法 降低眼内压可以减缓视力丧失青光眼的进展。在AD患者中， 脑中的神经病理学变化包括淀粉样蛋白β（Aβ）斑块和神经纤维缠结， 过度磷酸化的tau蛋白Aβ和tau也在两者的视神经（ON）和视网膜内观察到。 AD患者和青光眼患者。其他共同的疾病特征包括小胶质细胞激活和进行性 神经变性，其在青光眼中主要影响ON中的RGC及其轴突。 患青光眼的可能性比没有AD的人高出一倍。流行病学研究也检查了 青光眼患者发展为AD的风险，并已确定与年龄无关的关联， 或药物治疗。总之，这些发现表明了共享或协同机制的潜力 这两种疾病都是由它引起的潜在机制包括但不限于小胶质细胞 激活、蛋白质聚集和错误定位以及受损的树突和突触输入。我们假设 青光眼和AD协同作用，以加强神经炎症，AD样病理， 神经变性，加速进展和功能下降。但据 在老年人中观察到青光眼和AD的共同风险， 有其他年龄相关合并症的人群。考虑到这两个问题的严重累积负面影响， 疾病对老年人的健康，缺乏有效的治疗方法，迫切需要 提高对青光眼和AD相互作用的理解。为了解决我们的中心假设， 研究将询问特定眼和脑中的组织学、转录组学和蛋白质表达变化 在两种互补的青光眼模型（视神经挤压）中疾病进展过程中的区域 和眼内微珠注射诱导的高眼压）。 背景，将这些神经病理学变化与记忆、认知和 视野这些研究的成功将为AD和青光眼之间的相互作用提供机理上的见解， 阐明和优先考虑共享和新的目标，为新的治疗策略的开发提供信息， 减缓疾病进展并提高AD和青光眼患者生活质量。

Project Summary / Abstract: Alzheimer’s disease (AD) and glaucoma are two of the most prevalent age-related neurodegenerative disorders recognized worldwide. Globally, AD is the most widespread cause of dementia and a substantial cause of death, while glaucoma is the leading cause of irreversible blindness. In glaucoma, a characteristic optic neuropathy is associated with progressive visual field defects. There is currently no cure for either disease, although treatments that lower intraocular pressure can slow progression of vision loss glaucoma. In AD patients, characteristic neuropathologic changes in the brain include amyloid beta (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau. Aβ and tau have also been observed within the optic nerve (ON) and retina of both AD patients and glaucoma patients. Other shared disease features include microglial activation and progressive neurodegeneration, which in glaucoma primarily affects RGCs and their axons in the ON. AD patients are 2-3 times more likely to develop glaucoma than those without AD. Epidemiologic studies have also examined the risk for glaucoma patients to develop AD and have identified associations that are not attributable to age alone, or to medications. Together, these findings indicate the potential for shared or synergistic mechanisms responsible for, or contributing to, both diseases. Potential mechanisms include, but are not limited to, microglial activation, protein aggregation and mislocalization, and impaired dendritic and synaptic inputs. We hypothesize that glaucoma and AD act synergistically to intensify neuroinflammation, AD- like pathology, and neurodegeneration, accelerating progression and functional decline in both diseases. However, it is challenging to elucidate mechanisms for this observed shared risk for glaucoma and AD in older human populations with other age-associated co-morbidities. Given the profound cumulative negative impact of both diseases on the health of the aging population, and lack of effective therapies, there is an urgent need for improved understanding of the interaction of glaucoma and AD. To address our central hypothesis, the proposed studies will interrogate the histologic, transcriptomic and protein expression changes in specific eye and brain regions over the course of disease progression in two complementary models of glaucoma (optic nerve crush and ocular hypertension induced by intraocular microbead injection) in mice with normal and AD transgenic backgrounds, relating these neuropathologic changes to rate of functional decline in memory, cognition and vision. Success in these studies will provide mechanistic insight into the interaction between AD and glaucoma, illuminating and prioritizing shared and novel targets to inform the development of new therapeutic strategies to slow disease progression and enhance quality of life in AD and glaucoma patients.