Intersection of HSV-1 and microglial genetics in AD

Project Summary Alzheimer?s disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive decline and dementia. Genome-wide association studies have identified novel AD susceptibility loci. Interestingly the associated genes at several of these loci implicate the immune system in late-onset AD, specifically the innate immune system. Many recent lines of evidence suggest that the immune system plays a key role in AD initiation and progression, but the actual mechanistic dysfunction of the immune system in this neurodegenerative disease remains unknown. Genetic studies and pathology hint that the immune system?s ability to mount a productive response has been lost in AD with detrimental consequences. Post-mortem pathology of individuals with AD reveals an infiltration of T cells in the hippocampus, a region expected to be immune privileged, leading to speculation that AD might have an infectious component to its etiology or progression. In parallel, the pathogen hypothesis has garnered more support for a possible pathogenic etiology of AD. We propose to leverage our understanding of the immune system to determine if the immune response to the neuroinvasive pathogen human simplex virus (HSV)-1 is modulated by AD genetic associations, leading to increased risk for AD. We will take a comprehensive approach using cutting-edge tools to explore this hypothesis in AD. Combining genetics, human immunology, transcriptomics, virology, in vitro models, computational biology and epidemiology, we will dissect the interaction between HSV-1 infections and AD genetics. For this application, we propose a multifaceted approach using cutting-edge technology to: 1) identify the microglia response to HSV-1 infection based on each individual?s genetic background; 2) examine how these microglia function as antigen-presenting cells to T cells, a key cell type in resolving active infections; and 3) determine the interaction of HSV-1 and AD genetics in two well-establish cohorts and one anti-viral clinical trial in AD.