ALZHEIMER PATHOPHYSIOLOGY IN HUMAN CATARACT FORMATION

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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.