May 2004
Volume 45, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2004
Alzheimer's Disease ß–Amyloid (Aß) in the Lens: Interactions with AlphaB–Crystallin, Small Heat Shock Proteins, and Redox–Active Metal.
Author Affiliations & Notes
  • L.E. Goldstein
    Brigham & Women's Hospital, Boston, MA
    Harvard Medical School, Boston, MA
  • D. Hartley
    Brigham & Women's Hospital, Boston, MA
    Harvard Medical School, Boston, MA
  • J. Liang
    Brigham & Women's Hospital, Boston, MA
    Harvard Medical School, Boston, MA
  • J. Muffat
    Massachusetts General Hospital, Boston, MA
  • M. Rehrmann
    Brigham & Women's Hospital, Boston, MA
  • M. Ericsson
    Harvard Medical School, Boston, MA
  • G. Thurston
    Brigham & Women's Hospital, Boston, MA
  • M. Marcus
    Lawrence Berkeley National Laboratory, Berkeley, CA
  • A. Bush
    Harvard Medical School, Boston, MA
    Massachusetts General Hospital, Boston, MA
  • L. Chylack, Jr.
    Brigham & Women's Hospital, Boston, MA
    Harvard Medical School, Boston, MA
  • Footnotes
    Commercial Relationships  L.E. Goldstein, None; D. Hartley, None; J. Liang, None; J. Muffat, None; M. Rehrmann, None; M. Ericsson, None; G. Thurston, None; M. Marcus, None; A. Bush, None; L. Chylack, Jr., None.
  • Footnotes
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Investigative Ophthalmology & Visual Science May 2004, Vol.45, 3507. doi:
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      L.E. Goldstein, D. Hartley, J. Liang, J. Muffat, M. Rehrmann, M. Ericsson, G. Thurston, M. Marcus, A. Bush, L. Chylack, Jr.; Alzheimer's Disease ß–Amyloid (Aß) in the Lens: Interactions with AlphaB–Crystallin, Small Heat Shock Proteins, and Redox–Active Metal. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):3507.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Abstract: : Purpose: ß–amyloid (Aß) is critical to Alzheimer's disease (AD) pathogenesis. We identified Aß, amyloid pathology, and supranuclear cataracts in AD patient lens (Goldstein et al. Lancet, 2003). Aß organizes as e–dense cytosolic aggregates in AD lens fiber cells. Aß and alphaB–crystallin (ABC), a lens structural protein & small heat shock protein (sHSP)/molecular chaperone, show high–affinity association, cytosolic co–localization, and co–aggregation as birefringent, congophilic deposits. Aß and ABC co–localize with copper and zinc in neuritic plaque. Here we studied Aß interactions with ABC, sHSP, and metal. Methods: Western blot (WB), co–immunoprecipitation, turbidometry, thioflavin fluorescence, quasi–elastic light scattering, far–UV CD, atomic force microscopy (AFM), tryptic digest mass spec, metal histochemistry, EM autometallography, ICP–mass spec, x–ray fluorescence microscopy, immunogold EM (IEM), neurotoxicity. Results: We co–incubated Aß42 with human recombinant ABC, sHSP, or human lens protein extract. Aß42 incubated alone revealed discrete monomeric/low–order oligomeric WB bands; longer incubations showed fibril formation. Co–incubation of Aß42 with ABC or lens protein resulted in WB smears. Anti–Aß/ABC co–IP revealed discrete bands; tryptic digest–mass spec confirmed Aß/crystallin hetero–dimeric crosslinkage. We detected Aß/ABC heterodimers in human AD brain extract. Aß42/ABC (or sHSP) co–incubation increased turbidity, decreased ThT–fluorescence, and increased CD intensity vs control. Aß/ABC co–incubation blocked amyloid fibrillogenesis, facilitated protofibrils (PF) formation, and potentiated Aß neurotoxicity. AD lens revealed metal/Aß co–localization and confirmed cytosolic metal deposition. We initiated metal mapping (Cu, Zn, Fe) of human AD/non–AD lens using synchrotron/x–ray fluorescence microscopy. Aß potently promotes metal–dependent lens protein aggregation with increased light scattering. Conclusions: Aß interacts with ABC and redox–active metal to promote hetero–oligomeric lens protein aggregation. Aß interaction with ABC/sHSPs blocks amyloid fibrillogenesis but potentiates cytotoxic PF assembly. Molecular chaperones may stabilize pathogenic protein aggregate intermediates. sHSP–mediated PF stabilization and Aß/metal interactions may play critical roles in AD pathophysiology.

Keywords: aging • cataract • oxidation/oxidative or free radical damage 
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