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LE Goldstein, JA Muffat, RA Cherny, JA Coccia, I Delalle, MH Ericsson, RD Moir, RE Tanzi, AI Bush, LT Chylack; Beta-Amyloid Promotes Lens Protein Aggregation and is Associated with Supranuclear Lens Opacification . Invest. Ophthalmol. Vis. Sci. 2002;43(13):4802.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Alzheimer's disease (AD) is characterized by cerebral accumulation of extracellular protein aggregates composed predominantly of ß-amyloid peptides. We investigated AD-related lens pathology, demonstrated a unique cytosolic Aß localization, and further characterized lens Aß biochemistry. Methods:We examined neuropathologically-confirmed human AD lens specimens by slit lamp photomicroscopy. Other analyses included quantitative Aß Western blot, anti-Aß immunogold EM, α-crystallin/Aß co-immunoprecipitation analysis, and in vitro lens protein aggregation studies. Results: We studied a series of neuropathologcally-confirmed AD cases in which all cases to date demonstrated supranuclear/deep cortical cataracts, a relatively rare cataract phenotype (Chylack, 1984). Ultrastructural studies revealed Aß-immunoreactive microaggregates within the cytosol of lens fiber cells, the first demonstration of Aß in this compartment. We also observed apparent soluble monomeric and dimeric Aß species in adult human lens at levels comparable to brain. In contrast to our observation in the fiber cells, we did not observe Aß-immunoreactive microaggregates in lens epithelial cells or a human lens epithelial cell line. However, the epithelial cell line expressed proteins associated with Aß metabolism including ß-amyloid precursor protein (APP) and the LDL receptor-related protein (LRP). In addition, Aß is present in culture medium conditioned by this lens epithelial cell line. A proportion of lens Aß is bound to other lens proteins, including α-crystallin. Aß and αB-crystallin exhibited nanomolar intermolecular binding affinity in vitro and co-immunoprecipitated from human lens homogenates, indicating strong protein-protein association. Human Aß1-42 specifically promoted lens protein aggregation with increased ß-sheet content. Aß1-42-potentiated lens protein aggregation was blocked by specific metal chelators or reactive oxygen species scavengers, suggesting involvement of metalloprotein redox reactions.Conclusion: These data provide evidence for Aß-mediated lens protein aggregation and supranuclear cataract formation in Alzheimer's disease and suggest novel AD diagnostic and therapeutic interventions.
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