Abbreviations used: AD, Alzheimer's disease; Aβ, amyloid β-peptide; ALS, amyotrophic lateral sclerosis; apoE, apolipoprotein E; HNE, 4-hydroxynoneal; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; SDS, sodium dodecyl sulfate; SOD, superoxide dismutase.
A Mechanism for the Neuroprotective Effect of Apolipoprotein E
Isoform-Specific Modification by the Lipid Peroxidation Product 4-Hydroxynonenal
Article first published online: 18 JAN 2002
Journal of Neurochemistry
Volume 74, Issue 4, pages 1426–1433, April 2000
How to Cite
Pedersen, W. A., Chan, S. L. and Mattson, M. P. (2000), A Mechanism for the Neuroprotective Effect of Apolipoprotein E. Journal of Neurochemistry, 74: 1426–1433. doi: 10.1046/j.1471-4159.2000.0741426.x
- Issue published online: 18 JAN 2002
- Article first published online: 18 JAN 2002
- Alzheimer's disease;
- Amyotrophic lateral sclerosis;
- Oxidative stress;
- Spinal cord;
- Transgenic mice
Abstract: Inheritance of the apolipoprotein E (apoE) ε4 allele increases the risk for Alzheimer's disease and may also influence the pathogenesis of other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). The influence of apoE genotype on disease susceptibility must ultimately be explained by the fact that apoE proteins differ in only two amino acids: apoE2 has two cysteine residues, apoE3 has one cysteine residue, and apoE4 has none. We previously reported increased protein modification by the lipid peroxidation product 4-hydroxynonenal (HNE), which covalently binds to proteins on cysteine residues, in human ALS lumbar spinal cord. We now report increased levels of HNE-modified apoE in lumbar spinal cord samples from mice 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 isoforms to protect against apoptosis induced by HNE in cultures of mouse spinal cord motor neurons and by the amyloid β-peptide in cultures of rat hippocampal neurons. These data suggest that apoE plays a major role in detoxifying HNE, and the differential neuroprotective effect of its isoforms may help explain the relationship between apoE genotype and the susceptibility to neurodegenerative diseases.