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.

Grant Number: 5R01AG076018-05
NIH Institute/Center: NIH
Principal Investigator: Elizabeth Bradshaw