Oxidation of human apolipoprotein E and cerebral enzymatic systems

Apolipoprotein E (apoE) is a polymorphic protein whose specific isoform apo E4, has been widely associated with Alzheimer's disease (AD). ApoE may be l inked with this disease by its isoform-specific interaction with lipids or proteins of amyloid plaques such as amyloid-beta peptide (A beta). In addit ion, oxidative stress has been linked to the development of AD. Moreover, f ree radical production enhances the expression of genes encoding antioxidan t enzyme activities. Using the myeloperoxidase system, we previously report ed that the oxidation of the three recombinant apoE isoforms is differentia l, apoE4 being more susceptible than apoE3, and apoE3 itself more than apoE 2. ApoE-phospholipid complexes were prepared and we show that oxidation of apoE4 decreased its capacity to bind phospholipids. We also compared AP fib rillation in the presence of non-oxidized or oxidized apoE. Only oxidation of apoE4 enhanced AP fibrillation which could thus lead to inefficient lipi d recycling in the brain and enhance amyloid deposition in plaques. Glutath ione S-transferase (GST) is an important enzyme in antioxidant defense as i t removes compounds capable of generating reactive oxygen species. We compa red the activity of this enzyme in autopsy brains of AD patients as well as controls with no neuropathological disease in relation to the apoE genotyp e. GST activity is significantly increased in patients carrying an epsilon 4 allele. Cellular experiments are now required to determine apoE-GST funct ional relationships. These results strengthen the role of oxidation and the high linkage of the apoE epsilon 4 allele in AD.