ALZHEIMER PATHOPHYSIOLOGY IN HUMAN CATARACT FORMATION

老年性退行性疾病涉及阿尔茨海默病(AD)的病理生理，在老龄化的普通人群中呈上升趋势，并与氧化应激密切相关。AD生物学涉及退行性疾病的基本晶状体发育、氧化应激和程序性细胞死亡机制。我们的目标是开发干预AD病理生理学导致白内障的生物学后果的策略。利用全身氧化应激产生神经退化的体内模型，阿尔茨海默氏症蛋白也会在晶状体退行性变的区域积聚。阿尔茨海默病和普里恩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)通过产生空泡和晶状体细胞退化而对晶状体产生细胞毒性。晶状体中ABeta前体蛋白基因的分子生物学预测对AD病理生理的易感性增加，因为更有害的选择性剪接转录本，随着年龄和AD的增加而增加，并增加ABeta水平，在晶状体中占主导地位。我们的具体目标是：L)通过检测AD蛋白及其mRNAs，以及晶状体和暴露于ABeta的晶状体细胞的经典氧化应激细胞信号和转录因子参数，证明ABeta在晶状体氧化应激循环中的作用。2)通过检测AD和Prion蛋白在正常晶状体和白内障晶状体中的分布，确定AD基因产物与人类白内障形成的直接相关性。3)证实AD的表达与纤维细胞变性时ABeta含量的增加之间存在因果关系。首先，将完成对产生年龄相关性晶状体退化的人类ABeta前体蛋白转基因小鼠的分析。其次，为了直接测试ABeta在晶状体中的作用以及在体内AD氧化应激‘恶性循环’中的作用，将设计一种晶状体定向表达ABeta的小鼠。这些研究，加上AD蛋白在晶状体病理领域的增加，将确定AD病理生理学机制是白内障发生的重要因素，晶状体将成为人类全身退行性疾病中阿尔茨海默病病理生理学的易处理模型。

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.