Vulnerability of synaptosomes from ApoE knock-out mice to structural and oxidative modifications induced by A beta(1-40): Implications for Alzheimer's disease

Apolipoprotein E (apoE) plays an important role in the response to central nervous system injury. The e4 allele of apoE and amyloid beta -peptide (A b eta) are associated with Alzheimer's disease (AD) and may be central to the pathogenesis of this disorder. Recent studies demonstrate evidence for neu rodegeneration and increased lipid peroxidation in transgenic mice lacking apoE (KO). In the current study, synaptosomes were prepared from apoE KO mi ce to determine the role of apoE in synaptic membrane structure and to dete rmine susceptibility to oxidative damage by A beta (1-40). ApoE KO mice exh ibited structural modifications to lipid and protein components of synaptos omal membranes as determined by electron paramagnetic resonance in conjunct ion with lipid- and protein- specific spin labels. Incubation with 5 muM A beta (1-40) resulted in more severe oxidative modifications to proteins and lipids in apoE KO synaptosomes as measured by protein carbonyls, an index of protein oxidation, and TBARs and protein-bound 4-hydroxynonenal (HNE), m arkers of lipid oxidation. Together, these data support a role for apoE in the modulation of oxidative injury and in the maintenance of synaptic integ rity and are discussed with reference to alterations in AD brain.