Promotion of oxidative lipid membrane damage by amyloid β proteins

Senile plaques in the cerebral parenchyma are a pathognomonic feature of Alzheimer's disease (AD) and are mainly composed of aggregated fibrillar amyloid beta (A beta) proteins. The plaques are associated with neuronal degeneration, lipid membrane abnormalities, and chemical evidence of oxidative stress. The view that A beta proteins cause these pathological changes has been challenged by suggestions that they have a protective function or that they are merely byproducts of the pathological process. This investigation was conducted to determine whether A beta proteins promote or inhibit oxidative damage to lipid membranes. Using a mass spectrometric assay of oxidative lipid damage, the 42-residue form of A beta (A beta 42) was found to accelerate the oxidative lipid damage caused by physiological concentrations of ascorbate and submicromolar concentrations of copper(II) ion. Under these conditions, A beta 42 was aggregated, but nonfibrillar. Ascorbate and copper produced H2O2, but A beta 42 reduced H2O2 concentrations, and its ability to accelerate oxidative damage was not affected by catalase. Lipids could be oxidized by H2O2 and copper(II) in the absence of ascorbate, but only at significantly higher concentrations, and A beta 42 inhibited this reaction. These results indicate that the ability of A beta 42 to promote oxidative damage is more potent and more likely to be manifest in vivo than its ability to inhibit oxidative damage. In conjunction with prior results demonstrating that oxidatively damaged membranes cause A beta 42 to misfold and form fibrils, these results suggest a specific chemical mechanism linking A beta 42-promoted oxidative lipid damage to amyloid fibril formation.