Cerebrospinal fluid lipoproteins are more vulnerable to oxidation in Alzheimer's disease and are neurotoxic when oxidized ex vivo

Brain regional oxidative damage is thought to be a central mechanism in the pathogenesis of Alzheimer's disease (AD). Recent studies of cerebrospinal fluid (CSF) have suggested that increased lipid peroxidation of CSF and CSF lipoproteins also may occur in AD patients. In the present Study, we deter mined the susceptibility of human CSF to ex vivo lipid peroxidation and tes ted the hypothesis that oxidized CSF lipoproteins may be neurotoxic. Whole CSF or a CSF lipoprotein fraction (d < 1.210 g/mL) was oxidized with 2,2'-a zobis(2-amidinopropane)d dihydrochloride (AAPH), a hydrophilic free-radical generator. Kinetics of CSF lipid peroxidation were followed by a standard fluorescence product accumulation assay. Oxidation of AD CSF yielded signif icantly shorter fluorescent lag times than controls, indicating reduced ant ioxidant capacity. Electrophoretic mobilities of CSF apolipoproteins were s pecifically reduced upon oxidation of CSF with AAPH, suggesting that lipopr oteins are primary targets of CSF lipid peroxidation. Cultured neuronal cel ls were exposed to physiological concentrations of isolated CSF lipoprotein s oxidized with increasing concentrations of AAPH; the resulting neurotoxic ity showed a significant linear AAPH concentration-response relationship. T hese results suggest that oxidized CSF lipoproteins may contribute to the p athogenesis of neurodegeneration in AD.