Alzheimer's disease (AD) is a common and devastating
neurodegenerative disease in which most cases are of unknown, sporadic origin. In addition to age, the most prevalent known risk factor for developing AD is carriage of the epsilon4 allele of
Apolipoprotein E (
ApoE). Carriage of the epsilon2 or epsilon3 allele of
ApoE confers protection or no change in risk for AD, respectively. Latent herpes simplex virus type 1 (HSV-1)
infection in the brain concurrent with
ApoE4 carriage exacerbates risk for AD, suggesting that these two factors interact to promote neuronal dysfunction and degeneration in selective brain areas. Indeed, HSV-1
DNA has been found in regions primarily affected by AD, such as the temporal lobes, hippocampus, and neocortex. We hypothesize that HSV-1
infection in the background of
ApoE4, but not
ApoE2 or
ApoE3, promotes an environment more conducive to neuronal degeneration. To investigate this idea, we have utilized transgenic mice that express human
ApoE2, 3, or 4 alleles from astrocytes in a murine
ApoE -/- background. We find that carriage of the different
ApoE alleles dramatically affects HSV-1 immediate early gene expression as well as the establishment of latency. Both of these factors are poised to impact neuronal viability,
inflammation, and viral spread. Our data support the concept that HSV-1 and
ApoE4 interact to provide an environment conducive to the development and/or spread of AD.