A mechanism for the neuroprotective effect of apolipoprotein E: Isoform-specific modification by the lipid peroxidation product 4-hydroxynonenal

Inheritance of the apolipoprotein E (apoE) epsilon 4 allele increases the r isk for Alzheimer's disease and may also influence the pathogenesis of othe r neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). T he influence of apoE genotype on disease susceptibility must ultimately be explained by the fact that apoE proteins differ in only two amino acids: ap oE2 has two cysteine residues, apoE3 has one cysteine residue, and apoE4 ha s none. We previously reported increased protein modification by the lipid peroxidation product 4-hydroxynonenal (HNE), which covalently binds to prot eins on cysteine residues, in human ALS lumbar spinal cord, We now report i ncreased levels of HNE-modified apoE in lumbar spinal cord samples from mic e expressing an ALS-linked mutation in Cu/Zn-superoxide dismutase relative to controls. Studies of interactions of pure apoE proteins with HNE showed that the isoforms differ in the amount of HNE they can bind, with the order E2 > E3 > E4. This correlated with the differential ability of apoE isofor ms to protect against apoptosis induced by HNE in cultures of mouse spinal cord motor neurons and by the amyloid beta-peptide in cultures of rat hippo campal neurons. These data suggest that apoE plays a major role in detoxify ing HNE, and the differential neuroprotective effect of its isoforms may he lp explain the relationship between apoE genotype and the susceptibility to neurodegenerative diseases.