Alzheimer’s Disease Aβ Mediates Metal-Dependent Lens Protein Aggregation and Light Scattering

Abstract

Purpose: : Aβ peptide accumulation in the brain is a cardinal feature of Alzheimer’s disease (AD). We previously identified AD-linked Aβ deposition, amyloid pathology, and distinctive co-localizing subequatorial supranuclear cataracts in AD, but not in other neurodegenerative diseases or aged normal controls (Goldstein et al. Lancet, 2003). In AD, Aβ accumulates as e- dense hetero-oligomeric complexes in the lens fiber cell cytoplasm. Since AD pathogenesis involves Aβ metalloprotein chemistry, we hypothesized that related reactions contribute to Aβ-lens protein aggregation, light scattering, and cataractogenesis. Here, we provide definitive evidence of zinc accumulation in the cytoplasm of supranuclear lens fiber cells and show that this biometal potentiates Aβ-lens protein aggregation and light scattering. A mechanistic model of cataractogenesis in AD lens is proposed.

Methods: : X-ray fluorescence microscopy (XRFM; Advanced Light Source beamline 10.3.2, Lawrence Berkeley National Laboratory, Dir., M. Marcus); ICP-MS elemental, isotope dilution analyses (Center for Biometals & Metallomics [CBM], Boston University, Dir. L. Goldstein); metal histochemistry; EM autometallography, quasi-elastic light scattering.

Results: : Classical metal histochemistry identified a region of chelatable biometal accumulation in the equatorial bow region of aged human lens. XRFM analysis definitively identified a corresponding annular band of lenticular zinc. EM autometallography revealed cytosolic metal accumulation confirmed by elemental ICP-MS. In vivo 70-zinc isotope partition analysis demonstrated stable zinc pools in the lens relative to more labile exchangeable zinc in skin, cornea, and retina. Quasi-elastic light scattering analysis revealed metal-dependent Aβ-mediated lens protein aggregation.

Conclusions: : Aβ-potentiated lens protein aggregation critically involves interaction with biometals within the lens fiber cell cytoplasm. Two definitive analytical techniques (XRFM, ICP-MS) identify and localize zinc as a candidate biometal participant in amyloidogenic reactions and supranuclear cataractogenesis in AD lens. These data extend our previous work identifying Aβ-mediated pathology in the lens (Goldstein et al., Lancet, 2003) and provide a candidate pathogenic mechanism for regionally localized cataract formation in AD.

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