HSV-1 and beta-amyloid deposition

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Alzheimer's disease (AD) is a neurodegenerative disorder with progressive decline in cognitive functions leading to memory loss and dementia. It affects millions of Americans and causes significant morbidity and mortality. AD is characterized by the accumulation of amyloid-β-containing neuritic plaques and intracellular tau protein tangles in the brain. Growing evidence pinpoints a link between herpes simplex virus 1 (HSV-1) infection and AD. Notably, HSV-1 DNA is detectable in AD amyloid plaques in human brains, and antiviral acyclovir is reported to block the accumulation of the AD- associated proteins beta-amyloid. Multiscale transcriptome analysis of independent Alzheimer's cohorts in the USA suggests that AD pathology traits are closely coupled with neurovirulence factor γ134.5 encoded by HSV-1. However, the way through which HSV-1 is functionally involved remains largely unknown. We recently found that γ134.5 recruits and activates protein kinase Cδ, a host serine/threonine kinase that upregulates β-secretase and facilitates AD pathology. As viral γ134.5 also targets Beclin1 in the autophagy pathway, we hypothesize that viral activities mediated by HSV-1 may alter homeostasis of amyloid precursor protein and its metabolites through γ134.5 and facilitates the development of AD. As such, we will study viral regulation of amyloid-β generation a 3D human neural cell culture model of Alzheimer's disease. Recombinant HSV will be constructed to interrogate the expression of β-secretase. Furthermore, we will investigate amyloid-β clearance. Genetic studies will be carried out to assess viral interference of autophagy machineries. The proposed research will systematically explore pathological features of AD linked to HSV-1 infection. If successful, it will inform design of new therapeutic approach for AD.