Elizabeth M. Bradshaw, PhD

My research is focused on understanding the role of the innate immune system, including microglia, monocytes and macrophages, in complex neurodegenerative diseases. As a clinical immunologist, I work predominantly with human model systems, obtaining innate immune cells from both peripheral blood samples as well as from the CNS of individuals in order to characterize their phenotype and probe their functional capabilities. We are examining the immunological component of neurological disease with ex vivo RNA-sequencing of microglia¹, genotype induced phenotypes^2,3,4, and in vitro culture models². These highly collaborative projects are leading to a better understanding of innate immune cells in the human CNS as well as translating recent genome-wide association studies (GWAS) findings to functional outcomes and biological pathways that could be targeted for therapeutic intervention. A number of genetic loci associated with Alzheimer’s disease (AD) and Parkinson’s disease (PD) appear to exert their influence on disease through the innate immune system. Determining the molecular processes that these loci are manipulating in the innate immune system, and how that impacts susceptibility to AD and PD is a current focus of my laboratory. There is a fundamental need to better understand the molecular function of neurodegenerative-associated proteins, be they genetically associated or through other big data efforts, in innate immune cells.

When the original GWAS findings for AD were presented, the CD33 locus was among the initial hits. We then investigated the influence of the genetic variation on myeloid cell phenotype and determined that individuals with the Alzheimer’s disease associated rs3865444^CC risk genotype have increased expression of CD33 on the surface of their monocytes compared to those with the rs3865444^AA protective genotype⁴. The risk allele is also associated with diminished internalization of amyloid-β1-42 peptide, accumulation of neuritic amyloid pathology and fibrillar amyloid on in vivo imaging, and increased numbers of human microglia withsmall, thick processes, and a rounded morphology⁴. Through further investigation, we determined that individuals with the Alzheimer’s disease associated rs3865444^CC risk genotype actually only have increased expression of full-length CD33, the isoform containing the sialic acid binding domain, compared to those with the rs3865444^AA protective genotype⁵. We are continuing to examine CD33, its binding partners and other genetically associated proteins in order to understand how to best target them for therapeutic intervention.