Investigating the role of long-term latent herpes simplex virus infection on APOE4-associated Alzheimer's disease pathogenesis

Project Summary 47 million people worldwide are living with Alzheimer's disease (AD) or a related form of dementia. In the US alone, the annual health care costs for people with AD will exceed 1 trillion dollars by 2050. However, current treatments do not robustly prevent disease progression. The major risk factors for the late-onset form of AD are advanced age and possession of the ε4 allele of apolipoprotein E (APOE). Importantly, increasing data support the hypothesis that latent herpes simplex virus 1 (HSV-1) infection is also a risk factor, especially in combination with the APOE4 allele. This suggests that current antivirals may halt or delay neurodegenerative disease progression in APOE4 carriers who are infected with HSV-1. A major gap in the study of this association, however, is the absence of an HSV infection model reflecting the complexity of long-term latent infection, particularly in the context of APOE4 and AD. In our preliminary studies, we observed that HSV-1-infected APOE4 mice, compared to mock-infected APOE4 mice and HSV-1-infected WT mice, displayed robust spatial memory deficits, as well as oxidative stress, iron dysregulation, and gliosis in the CNS when assessed 15 months post infection (mpi), but not at 3 mpi. The objective of this proposal is to use this model, as well as complementary in vitro models, to fully elucidate the effects of long-term latent HSV-1 infection, in the context of differential APOE isoform expression, on brain function and AD pathogenesis. We will also assess whether treatment with a novel, brain-penetrant antiviral medication can block these effects. We anticipate that the full study proposed herein will uncover unique and important interactions between HSV-1 infection and APOE genotype in driving AD pathogenesis, potentially leading to safe and effective new therapeutic strategies for preventing or slowing AD in at-risk individuals.