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L. Fu, E. Blakely, M. Marcus, K. Bjornstad, B. Due, M. Rehrmann, D. Hartley, G. Thurston, L.T. Chylack, Jr, L.E. Goldstein; Alzheimer’s Disease ß–Amyloid (Aß) Mediates Metal–Dependent Human Lens Protein Aggregation and Light Scattering . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2906.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Cerebral ß–amyloid (Aß) accumulation is a cardinal feature of Alzheimer's disease (AD). We have previously identified Aß, amyloid pathology, and co–localizing equatorial supranuclear cataracts (SNC) in human AD lenses (Goldstein et al., Lancet, 2003) and noted similar SNC phenotype and lenticular human Aß overexpression in Tg2576 transgenic mice (Goldstein et al., IOVS 2001; 42:ARVO Abst 1614). Lens Aß accumulates within equatorial fiber cells as e– dense cytosolic aggregates. Aß binds cytoplasmic lens proteins including αB–crystallin. Aß and αB–crystallin co–localize in the cytosol and co–aggregate as birefringent congophilic deposits. Since Aß sequesters copper and zinc in cerebral neuritic plaque and both metals promote Aß aggregation, we hypothesized that metalloprotein interactions may be involved in Aß–mediated lens protein aggregation. To test this hypothesis, we (1) performed metal mapping analyses in unfixed, cryopreserved human and Tg2576 lenses, and (2) studied the metalloprotein biochemistry of Aß–mediated lens protein aggregation. Methods: Cryofixation/section, synchrotron X–ray fluorescence microscopy, EM autometallograpy, ICP–mass spectrometry, metal histochemistry, atomic force microscopy, quasi–elastic light scattering, co–immunoprecipitation, crosslinkage analysis. Results: Copper, iron, and zinc are present in the cytosolic fraction of aged human lenses (1.8, 2.0, 27 µg/g protein, respectively). Aß and metal (especially zinc) co–localize within the cytoplasm of equatorial supranuclear lens fiber cells. Human Aß42 potently and specifically promotes metal–dependent lens protein aggregation and increased light scattering. Aß–mediated lens protein aggregation is critically dependent on metalloprotein redox chemistry. Conclusions: Lens Aß promotes hetero–oligomeric cytosolic lens protein aggregation via protein–protein interactions and metalloprotein redox reactions. Once formed, Aß–associated lens protein aggregates scatter light that manifest as the SNC phenotype. We hypothesize that SNC and its molecular antecedents are early, organ–specific expressions of the same underlying AD disease process evident in the brain. Acknowledgments: NIA, Mass Lion’s Eye Res Fund, Mass Alz Disease Res Center (NIA), Brigham & Women’s Hospital, anonymous foundation.
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