Herpes simplex virus type 1, apolipoprotein E, and cholesterol: a dangerous liaison in Alzheimer's disease and other disorders

Abstract

Almost a hundred years ago, the main neuropathological features of Alzheimer's disease (AD) brain were discovered, yet the underlying cause(s) are still unknown, and the disease is basically untreatable. Despite the very numerous studies on the neuropathological features, the cause(s) of their production and whether they have an aetiological role in the disease or are merely end-products ("tombstones") are still unknown. Indeed, until fairly recently, the only known risk factors were age, Down's syndrome and head injury. A susceptibility factor, the type 4 allele of the apolipoprotein E gene was identified, but it is neither essential nor sufficient to cause AD, so other factors must be involved also. We investigated the possibility of a viral role and discovered that HSV1 DNA is present in brain of a high proportion of elderly people and that in combination with APOE-epsilon4 it confers a high risk of AD. Subsequently, we found that APOE determines outcome of infection in several diseases caused by diverse infectious agents. Here we describe our studies, and the few others carried out elsewhere, on the mechanism of action of HSV1 and the dependence of the damage on APOE. We discuss, in relation to HSV1 action on lipids and to the spread of the virus via lipid rafts in brain, the possible involvement in AD of cholesterol, a vital and major component of the human brain, and the dispute over whether statins, drugs used for lowering cholesterol levels, are protective against the disease. We also link the damage due to two major consequences of HSV1 infection--inflammatory and oxidative processes--to lipid peroxidation in brain, and consider the influence of the different apoE isoforms in this process.