DISTRIBUTION OF REDUCIBLE 4-HYDROXYNONENAL ADDUCT IMMUNOREACTIVITY INALZHEIMER-DISEASE IS ASSOCIATED WITH APOE GENOTYPE

Two major risk factors for late-onset familial and sporadic Alzheimer disease (AD), a leading cause of dementia worldwide, are increasing ag e and inheritance of the epsilon 4 allele of the apolipoprotein E gene (APOE4). Several isoform-specific effects of apoE have been proposed; however, the mechanisms by which apoE isoforms influence the pathogen esis of AD are unknown. Also associated with AD is increased lipid per oxidation in the regions of the brain most damaged by disease. 4-hydro xynonenal (HNE), the most potent neurotoxic product of lipid peroxidat ion, is thought to be deleterious to cells through reactions with prot ein nucleophiles. We tested the hypothesis that accumulation of the mo st common forms of HNE-protein adducts, borohydride-reducible adducts, is associated with AD and examined whether there was a relationship t o APOE. Our results demonstrated that reducible HNE adducts were incre ased in the hippocampus, entorhinal cortex, and temporal cortex of pat ients with AD. Furthermore, our data showed that the pattern of reduci ble HNE adduct accumulation was related to APOE genotype; AD patients homozygous for APOE4 had pyramidal neuron cytoplasmic accumulation of reducible HNE adducts, while AD APOE3 homozygotes had both pyramidal n euron and astrocyte accumulation of reducible HNE adducts. This is in contrast to our previous observations that a distinct HNE protein addu ct, the pyrrole adduct, accumulates on neurofibrillary tangles in AD p atients. We conclude that APOE genotype influences the cellular distri bution of increased reducible HNE adduct accumulation in AD.