ALZHEIMER PATHOPHYSIOLOGY IN HUMAN CATARACT FORMATION

阿尔茨海默病（AD）病理生理学相关的退行性疾病在老年人群中不断增加，并与氧化应激密切相关。AD生物学涉及退行性疾病中的基本透镜发育、氧化应激和程序性细胞死亡机制。我们的目标是制定策略，干预AD病理生理学导致白内障的生物学后果。使用产生神经变性的全身性氧化应激的体内模型，阿尔茨海默蛋白也在透镜变性的区域中积累。阿尔茨海默病和朊病毒病蛋白随着氧化应激和经典氧化应激细胞反应的平行激活而增加。β-淀粉样蛋白（ABeta）通过产生空泡和透镜细胞变性对透镜具有细胞毒性。透镜中ABeta前体蛋白基因的分子生物学预测了对AD病理生理学的高度易感性，因为随着衰老和AD而增加并增加ABeta水平的更有害的选择性剪接转录物在晶状体中占主导地位。我们的具体目标是：l）通过测定暴露于ABeta的晶状体和透镜细胞中的AD蛋白及其mRNA以及经典氧化应激细胞信号传导和转录因子参数，证明ABeta在透镜中的氧化应激循环中的作用。2)通过确定正常和白内障患者晶状体中AD和朊病毒蛋白的分布，确定AD基因产物与白内障形成的直接相关性。 3)证明AD表达和ABeta量增加与纤维细胞变性之间的因果关系。首先，将完成对产生年龄相关透镜变性的人ABeta前体蛋白转基因小鼠的分析。第二，为了直接测试ABeta在透镜中和在体内AD氧化应激“恶性循环”中的作用，将工程化具有透镜定向的ABeta表达的小鼠。这些研究以及AD蛋白在透镜病理学领域增加的证明，将定义AD病理生理学机制为白内障发生的重要贡献者，并将透镜定义为人体全身退行性疾病中阿尔茨海默病病理生理学的易于处理的模型。

Age-related degenerative disease involving Alzheimer's disease (AD) pathophysiology is increasing in the aging general population, and is closely associated with oxidative stress. AD biology is involved in basic lens development, oxidative stress, and programmed cell death mechanisms in degenerative diseases. Our goal is to develop strategies to intervene in the biological consequences of AD pathophysiology contributing to cataract. Using an in vivo model of systemic oxidative stress that produces neurodegeneration, Alzheimer proteins also accumulate in areas of lens degeneration. Alzheimer and prion disease proteins increase with oxidative stress and parallel activation of classic oxidative stress cellular responses. Beta-amyloid (ABeta) is cytotoxic to the lens by producing vacuoles and lens cell degeneration. The molecular biology of the ABeta precursor protein gene in the lens predicts heightened susceptibility to AD pathophysiology, since the more deleterious alternatively spliced transcripts, that increase with aging and AD, and increase ABeta levels, predominate in lenses. Our specific aims are: l) Demonstrate ABeta's role in the oxidative stress cycle in lens by assaying AD proteins and their mRNAs, and classic oxidative stress cell-signaling and transcription factor parameters in lenses and lens cells exposed to ABeta. 2) Establish the direct relevance of AD gene products in human cataract formation by determining AD and prion protein distribution in normal and cataractous human lenses. 3) Demonstrate a causal relationship between AD expression and increased ABeta amounts with fiber cell degeneration. First, the analysis of the human ABeta precursor protein transgenic mouse that produces age- related lens degeneration will be completed. Second, to directly test ABeta action in lens and in the AD oxidative stress 'vicious cycle' in vivo, a mouse with lens-directed ABeta expression will be engineered. These studies, together with the demonstration of AD proteins increases in areas of lens pathology, will define mechanisms of AD pathophysiology as significant contributors to cataractogenesis, and the lens as a tractable model of Alzheimer pathophysiology in human degenerative disease throughout the body.