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

项目摘要/摘要： 阿尔茨海默病(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 举世公认。在全球范围内，阿尔茨海默病是痴呆症最普遍的原因，也是导致死亡的重要原因， 而青光眼是导致不可逆性失明的主要原因。在青光眼中，一种典型的视神经病变是 与进行性视野缺陷相关。目前还没有治愈这两种疾病的方法，尽管治疗方法 较低的眼压可以减缓失明青光眼的进展。在AD患者中，特征 大脑中的神经病理变化包括淀粉样β蛋白(Aβ)斑块和神经纤维缠结 过度磷酸化的tau。在两者的视神经和视网膜中也观察到了β和tau。 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 神经退行性变，在青光眼中主要影响视网膜节细胞及其轴突。AD患者年龄为2-3岁 患青光眼的可能性是那些没有AD的人的三倍。流行病学研究还检查了 青光眼患者患阿尔茨海默病的风险，并已确定与年龄无关， 或药物治疗。总之，这些发现表明了共享或协同机制的潜力 导致或促成这两种疾病的。可能的机制包括，但不限于，小胶质细胞 激活、蛋白质聚集和错误定位，以及树突状细胞和突触输入受损。我们假设 青光眼和阿尔茨海默病协同作用，加剧神经炎症，AD样病理，以及 在这两种疾病中，神经退行性变、进展加速和功能下降。然而，它是 要阐明这种观察到的老年人青光眼和阿尔茨海默病共同风险的机制具有挑战性 有其他与年龄相关的共病的人群。鉴于这两个因素的深刻累积负面影响 疾病对老龄化人口健康的影响，以及缺乏有效的治疗方法，迫切需要 提高了对青光眼和阿尔茨海默病相互作用的理解。为了解决我们的中心假设，建议的 研究将询问特定眼睛和大脑的组织学、转录和蛋白质表达的变化 两种互补的青光眼模型(视神经挤压)的病程区域 和眼内注射微珠引起的高眼压)正常和AD转基因小鼠 背景，将这些神经病理变化与记忆、认知和功能减退的比率联系起来 幻象。这些研究的成功将为AD和青光眼之间的相互作用提供机械性的洞察， 阐明和优先考虑共同的和新的靶点，以便为开发新的治疗策略提供信息 延缓阿尔茨海默病和青光眼患者的疾病进展，提高生活质量。

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.