December 2002
Volume 43, Issue 13
Free
ARVO Annual Meeting Abstract  |   December 2002
Beta-Amyloid Promotes Lens Protein Aggregation and is Associated with Supranuclear Lens Opacification
Author Affiliations & Notes
  • LE Goldstein
    Center for Ophthalmic Research Brigham & Women's Hospitals Harvard Medical School Boston MA
  • JA Muffat
    Mass Gen Hosp Charlestown MA
    Lab for Oxidation Biology/Genetics & Aging Unit
  • RA Cherny
    University of Melbourne Melbourne Australia
  • JA Coccia
    Mass Gen Hosp Charlestown MA
    Lab for Oxidation Biology/Genetics & Aging Unit
  • I Delalle
    Dept of Neuropathology
    Mass Gen Hosp Charlestown MA
  • MH Ericsson
    Harvard Med School Boston MA
  • RD Moir
    Genetics & Aging Unit
    Mass Gen Hosp Charlestown MA
  • RE Tanzi
    Genetics & Aging Unit
    Mass Gen Hosp Charlestown MA
  • AI Bush
    Mass Gen Hosp Charlestown MA
    Lab for Oxidation Biology/Genetics & Aging Unit
  • LT Chylack
    Center for Ophthalmic Research Brigham & Women's Hospitals Harvard Medical School Boston MA
  • Footnotes
    Commercial Relationships   L.E. Goldstein, None; J.A. Muffat, None; R.A. Cherny, None; J.A. Coccia, None; I. Delalle, None; M.H. Ericsson, None; R.D. Moir, None; R.E. Tanzi, None; A.I. Bush, None; L.T. Chylack, None. Grant Identification: NIH EY12015, MA Lion's Eye Res.Fund, Health & Medical Res. Council (AU), Brigham & Women's Hosp.
Investigative Ophthalmology & Visual Science December 2002, Vol.43, 4802. doi:
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    • Get Citation

      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)

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Abstract

Abstract: : 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.

Keywords: 338 cataract • 309 aging • 352 clinical (human) or epidemiologic studies: natural history 
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