Amyloid b-peptide(1-42)-induced oxidative stress and neurotoxicity: Immplications for neurodegeneration in Alzheimer’s disease brain. A review. Free Radic

Oxidative stress, manifested by protein oxidation, lipid peroxidation, DNA oxidation and 3-nitrotyrosine formation, among other indices, is observed in Alzheimer’s disease (AD) brain. Amyloid b-peptide (1–42) [Ab(1–42)] may be central to the pathogenesis of AD. Our laboratory and others have implicated Ab(1–42)-induced free radical oxidative stress in the neurodegeneration observed in AD brain. This paper reviews some of these studies from our laboratory. Recently, we showed both in-vitro and in-vivo that methionine residue 35 (Met-35) of Ab(1–42) was critical to its oxidative stress and neurotoxic properties. Because the C-terminal region of Ab(1–42) is helical, and invoking the i 1 4 rule of helices, we hypothesized that the carboxyl oxygen of lle-31, known to be within a van der Waals distance of the S atom of Met-35, would interact with the latter. This interaction could alter the susceptibility for oxidation of Met-35, i.e. free radical formation. Consistent with this hypothesis, substitution of lle-31 by the helixbreaking amino acid, proline, completely abrogated the oxidative stress and neurotoxic properties of Ab(1–42). Removal of the Met-35 residue from the lipid bilayer by substitution of the negatively charged Asp for Gly-37 abrogated oxidative stress and neurotoxic properties of Ab(1–42). The free radical scavenger vitamin E prevented A