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

青光眼和阿尔茨海默病交叉的疾病机制

• 批准号: 10306895
• 负责人: Gillian Jane McLellan
• 金额: $ 41.43万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10306895
• 关键词: Abeta clearance; Address; Affect; Age; Age-Months; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; American; Amyloid beta-Protein; Animal Model; Animals; Axon; Behavioral Assay; Blindness; Brain; Brain region; Cause of Death; Characteristics; Chronic; Clinical; Clinical Management; Cognition; Cognitive; Complex; Data; Data Set; Dementia; Deposition; Development; Diagnosis; Disease; Disease Progression; Dissection; Elderly; Enzyme-Linked Immunosorbent Assay; Exhibits; Eye; Felis catus; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Glaucoma; Health; Hippocampus (Brain); Histologic; Human; Impaired cognition; Impairment; In Situ Hybridization; Inflammatory; Injections; Measures; Memory; MicroRNAs; Microglia; Microspheres; Midbrain structure; Modeling; Molecular; Mus; National Institute on Aging; Nerve Crush; Nerve Degeneration; Nerve Tissue; Neuraxis; Neurocognitive Deficit; Neurodegenerative Disorders; Neurofibrillary Tangles; Ocular Hypertension; Optic Disk; Optic Nerve; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Physiologic Intraocular Pressure; Population; Prevalence; Quality of life; Reporting; Resource Sharing; Retina; Retinal Ganglion Cells; Risk; Scotoma; Senile Plaques; Sex Differences; Synapses; Thalamic structure; Time; Transgenic Mice; Transgenic Organisms; Vision; Visual Cortex; abeta accumulation; abeta deposition; age related; age related neurodegeneration; aging population; animal tissue; base; comorbidity; conditioned fear; differential expression; economic cost; effective therapy; epidemiology study; functional decline; functional outcomes; high risk; human old age (65+); hyperphosphorylated tau; improved; in vivo; inflammatory marker; insight; mouse model; neuroinflammation; neuropathology; neurotoxic; next generation sequencing; novel; novel therapeutic intervention; optic nerve disorder; progressive neurodegeneration; protein aggregation; protein expression; public health relevance; research clinical testing; risk sharing; sex; success; superior colliculus Corpora quadrigemina; tau Proteins; therapeutic target; transcriptome sequencing; transcriptomics; white matter

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.

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 在全球范围内，AD 是痴呆症最常见的原因，也是导致死亡的重要原因。 青光眼是导致不可逆性失明的主要原因。青光眼的特征是视神经病变。 尽管有治疗方法，但目前尚无法治愈这两种疾病。 降低眼压可以减缓 AD 患者视力丧失的进展。 大脑中的神经病理变化包括β淀粉样蛋白（Aβ）斑块和神经原纤维缠结 在两者的视神经 (ON) 和视网膜中也观察到了过度磷酸化的 tau 蛋白。 AD 患者和青光眼患者的其他共同疾病特征包括小胶质细胞激活和进行性。 青光眼中的神经变性主要影响 AD 患者的 RGC 及其轴突，为 2-3 个。 流行病学研究也检查了患青光眼的可能性是没有 AD 的人的几倍。 青光眼患者患 AD 的风险，并已确定与年龄无关的关联， 这些发现共同表明了共享或协同机制的潜力。 造成或促成这两种疾病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树突和突触输入受损。 青光眼和 AD 协同作用，加剧神经炎症、AD 样病理学，以及 然而，这两种疾病的神经退行性疾病都会加速进展和功能衰退。 阐明老年人患青光眼和 AD 的共同风险的机制具有挑战性 考虑到这两种疾病的累积负面影响，患有其他与年龄相关的并发症的人群。 老年人口健康受到影响的疾病，且缺乏有效的治疗方法，迫切需要 更好地了解青光眼和 AD 之间的相互作用。 研究将探究特定眼睛和大脑的组织学、转录组和蛋白质表达变化 两种互补的青光眼模型（视神经挤压）在疾病进展过程中的区域 和眼内微珠注射诱导的高眼压）在正常小鼠和 AD 转基因小鼠中 背景，将这些神经病理学变化与记忆、认知和功能下降的速度联系起来 这些研究的成功将为 AD 和青光眼之间的相互作用提供机制上的见解， 阐明并优先考虑共享和新颖的目标，为新治疗策略的开发提供信息 减缓疾病进展并提高 AD 和青光眼患者的生活质量。