ALZHEIMER PATHOPHYSIOLOGY IN HUMAN CATARACT FORMATION

年龄相关的退行性疾病包括阿尔茨海默病（AD）的病理生理在老龄化人群中不断增加，并且与氧化应激密切相关。AD生物学涉及退行性疾病的晶状体发育、氧化应激和程序性细胞死亡机制。我们的目标是制定策略，干预阿尔茨海默病病理生理导致白内障的生物学后果。在体内系统氧化应激产生神经变性的模型中，阿尔茨海默氏蛋白也在晶状体变性区域积累。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）通过产生液泡和晶状体细胞变性对晶状体具有细胞毒性。晶状体中ABeta前体蛋白基因的分子生物学预测了对AD病理生理的易感性增加，因为随着年龄和AD增加的更有害的选择性剪接转录物和增加的ABeta水平在晶状体中占主导地位。我们的具体目标是：1)通过分析AD蛋白及其mrna，以及暴露于ABeta的晶状体和晶状体细胞中的经典氧化应激细胞信号传导和转录因子参数，证明ABeta在晶状体氧化应激循环中的作用。2)通过测定正常和白内障晶状体中AD和朊蛋白的分布，建立AD基因产物与白内障形成的直接相关性。3)证明AD表达与纤维细胞变性中β量增加之间的因果关系。首先，完成对产生年龄相关性晶状体变性的人β前体蛋白转基因小鼠的分析。其次，为了在体内直接测试ABeta在晶状体和AD氧化应激“恶性循环”中的作用，将设计一只晶状体定向表达ABeta的小鼠。这些研究，再加上晶状体病理领域中AD蛋白的增加，将确定AD病理生理机制是白内障发生的重要因素，晶状体是整个人体退行性疾病中阿尔茨海默病病理生理的可处理模型。

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.