Role of Latent Human Herpesvirus 6 Infection in Alzheimer Disease
Whole virions can be found in hOPC after infection.
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease. The vast majority of cases are sporadic and are thought to be caused by a combination of multiple genetic and environmental factors. Viral infections have long been implicated as a possible risk factor for Alzheimer’s disease, but their contribution remains unclear. We have been studying the impact of human Herpesvirus 6A (HHV6A) on cells of the central nervous system (CNS) and identified a number of processes in host cells that are impaired by latent HHV6 infections. We find that expression of U94A, the major latency associated gene, in human primary oligodendrocyte progenitor cells (OPCs) inhibits their migration and maturation into oligodendrocytes, and expression of U94A in primary human neurons impairs neurite complexity and leads to synapse loss. These and other defects are particularly relevant for the early stages of Alzheimer disease, as mounting evidence suggests that Alzheimer disease is primarily a disease of synapse and neurite loss, associated with diffuse demyelination. Based on these observations, we hypothesize that expression of U94A in the brain, represents a disease-modifying factor that increases vulnerability of neuronal and glia cell, and exacerbates or accelerates pathology in patients otherwise predisposed to AD. To test this hypothesis, we established Alzheimer disease-patient derived cell culture systems that allow for co-expression of U94A and produced a U94A transgenic mouse to circumvent the lack of CNS latency in mice following primary HHV6 infections. Using these tools, we work in collaboration with Dr. Chris Proschel (U of R) and Orlu Lazarov ( U of Chicago) to determine expression of U94A in neurons and glial cells derived from Familial Alzheimer disease (FAD) patients will worsen cellular pathologies, to test the impact of U94A expression on the cellular pathologies in vivo and to test the hypothesis that expression of U94A in animal models of FAD leads to accelerated onset or exacerbated, AD-associated cognitive defects.