April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Zinc Potentiates Alzheimer’s Disease Amyloid-β (Aβ)-Mediated Lens Protein Aggregation and Light Scattering
Author Affiliations & Notes
  • Lee E. Goldstein
    Molecular Aging and Development Laboratory, Boston University, Boston, Massachusetts
    Center for Biometals & Metallomics, Boston University, Boston, Massachusetts
  • Noel Casey
    Center for Biometals & Metallomics, Boston University, Boston, Massachusetts
    Molecular Aging & Development Laboratory, Boston, Massachusetts
  • Matthew A. Marcus
    Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, California
  • John C. Voss
    Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California
  • Robin Altman
    Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California
  • Juliet A. Moncaster
    Molecular Aging and Development Laboratory, Boston University, Boston, Massachusetts
  • Footnotes
    Commercial Relationships  Lee E. Goldstein, Neuroptix (Acton, MA) (C, P); Noel Casey, None; Matthew A. Marcus, None; John C. Voss, None; Robin Altman, None; Juliet A. Moncaster, None
  • Footnotes
    Support  LG: NIGMS R01GM075986, NCRR 1S10RR026599, 5P41RR010888); NSF 0821304, NIH Alzheimer’s Dis Center P30AG013846; Cure Alzheimer’s Fund; Boston University. JV: NIA 5R01AG029246.
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 807. doi:https://doi.org/
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    • Get Citation

      Lee E. Goldstein, Noel Casey, Matthew A. Marcus, John C. Voss, Robin Altman, Juliet A. Moncaster; Zinc Potentiates Alzheimer’s Disease Amyloid-β (Aβ)-Mediated Lens Protein Aggregation and Light Scattering. Invest. Ophthalmol. Vis. Sci. 2011;52(14):807. doi: https://doi.org/.

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

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Abstract

Purpose: : Cerebral accumulation of amyloid-β (Aβ) is a cardinal feature of Alzheimer’s disease (AD) and Down syndrome (DS). AD-linked protein aggregation in the brain is mediated via Aβ metalloprotein interactions. We previously reported Aβ deposition, AD-associated amyloid pathology, and co-localizing equatorial supranuclear cataracts (SNC) in the ocular lenses of subjects with AD (Goldstein et al., Lancet, 2003) and DS (Moncaster et al., Plos One, 2010). These data are the first to establish AD-linked amyloid pathology outside the brain, strongly support the hypothesis that AD is a systemic disorder, pave the way for development of novel ophthalmic technology for early AD detection and diagnosis. Here we studied Aβ interactions with biometals in the lens.

Methods: : Human lenses (AD, DS, age-matched normal and non-AD/DS disease controls) obtained with IRB approval. Metallomic imaging mass spectrometry (MIMS, Center for Biometals & Metallomics, Boston, MA), X-ray fluorescence microscopy (Advanced Light Source beamline 10.3.2, LBNL, Berkeley, CA), metal histochemistry, EM autometallography, quasi-elastic light scattering (QLS), turbidometry, electron paramagnetic resonance (EPR).

Results: : Metallomic analysis of human AD and DS lenses definitively identified and co-localized zinc and Aβ in the same cytosolic compartment of subequatorial supranuclear lens fiber cells. QLS and turbidometric analyses demonstrated that zinc potently and dose-dependently potentiates Aβ-mediated lens protein aggregation. EPR analysis confirmed the pro-aggregation effect and revealed a corresponding potentiating effect on Aβ and Aβ-crystallin interaction. Chelation blocked Aβ-mediated lens protein aggregation and QLS signal changes.

Conclusions: : These results demonstrate that bioavailable lenticular zinc: (i) accumulates in the cytosol of AD/DS supranuclear lens fiber cells, (ii) potentiates Aβ-mediated lens protein aggregation, and (iii) contributes mechanistically to expression of the distinctive age-dependent supranuclear lens phenotype associated with AD and DS. Taken together, these data identify zinc as a candidate biometal participant in AD/DS-associated amyloidogenic reactions and provide further support linking AD/DS-associated Aβ-mediated pathology in the lens and brain.

Keywords: cataract • pathology: human • pathobiology 
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