Oxidized lipoproteins, beta amyloid peptides and alzheimer's disease

Recent studies have provided strong evidence for the involvement of oxidative stress in the pathogenesis of Alzheimer's disease (AD) and beta-amyloid peptides (Ap) have been implicated to play an important role in mediating these oxidative events. Lipoproteins (LP) in the brain are likely targets of oxidative insult and together enhance Ap-mediated toxicity to neurons. We hypothesize that uptake of oxidized LP by neuron leads to an acceleration of the intracellular oxidative pathways and exacerbation of neuron cell death. In our previous studies, we demonstrated the ability of oxidized low-density LP from plasma to induce cell death in PC12 cells. In this study, a synthetic LP fraction was prepared using lipids extracted from rat brain and incubated with albumin and apoE. This brain lipid-derived LP (BLP) was subjected to oxidation by incubation with Fe3+ and subsequently tested with primary cortical neurons in culture. To study uptake of the BLP, native and oxidized BLP containing apoE3 or apoE4 were labeled with [C-14]cholesterol or the fluorescent probe 3,3-dioctadecylindo-carbocy-anine (Di-I) prior to exposing to cultured neurons. Results showed that regardless of the labeling method, oxidized BLP were more effectively taken up by the neurons than the native BLP. Cell viability was assessed by assaying the release of lactate dehydrogenase (LDH) into the medium and by determining the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphe-nyltetrazolium bromide (MTT), an agent depicting mitochondrial activity. While exposure of neurons to oxidized BLP and aggregated A6 (1-42) alone could result in MTT reduction (24%), greater reduction (40%) could be observed when oxidized LP was added together with Ap. Neuronal cell death due to oxidized BLP could be ameliorated by resveratrol, a polyphenolic compound known for its antioxidant properties. Taken together, these results are in agreement with the notion that Ap and oxidized BLP can synergistically enhance oxidative damage in neurons and antioxidants such as resveratrol can ameliorate these damages.