Viruses and apolipoprotein E: a dangerous liaison for Alzheimer's disease and several infectious diseases
We aimed to find if the APOE gene modulates severity of, or susceptibility to, infection by diverse pathogens. This followed our discovery that herpes simplex type 1 (HSV1) resides in many elderly brains [Jamieson et al., 1991], and that in carriers of the type 4 APOE allele it confers a high risk of Alzheimer’s disease; also, APOE-e4 is a risk for cold sores [Itzhaki et al., 1997]).
We investigated diseases caused by pathogens (HSV1, hepatitis C virus (HCV) and malaria protozoon) that bind to the same cell surface molecules as the protein apoE - heparan sulphate proteoglycans (HSPG), and/or an apoE receptor. We hypothesised that pathogen and protein compete for binding and entry, and that binding differences amongst the apoE isoforms determine extent of pathogen entry, spread, and damage.
We found that in HSV1 encephalitis, APOE-e2 is a risk [Lin et al., 2001]. With HCV-induced liver damage, APOE-e4 is highly protective, especially for males – but APOE does not influence susceptibility to infection, viral clearance, or non-viral liver damage [Wozniak et al., 2002. Preliminary data for malaria suggest that APOE-e2 homozygotes are infected at an especially early age [Wozniak et al., 2003].
We have now compared diseases caused by two other herpesviruses - varicella zoster virus (VZV), and Epstein-Barr virus (EBV); VZV binds to HSPG whereas EBV does not – nor to an apoE receptor. Consistently, we found that APOE-e4 is protective against post-herpetic neuralgia (for females), though not affecting shingles, and APOE does not affect infectious mononucleosis.
We conclude that the seemingly paradoxical effects of e4 and e2 – variously protective or harmful - might reflect a dependence of the binding affinity of apoE isoforms on cell type [Itzhaki et al., 2004]. Our APOE results demonstrate strikingly the diverse interactions of a gene with environmental factors. Our AD data demonstrate strikingly the influence of an environmental factor on a chronic disease.