Elizabeth M. Bradshaw, PhD

Academic Appointments

  • Adler Assistant Professor of Neurological Sciences (in Neurology, the Taub Institute, and the Institute for Genomic Medicine)
Elizabeth M. Bradshaw, PhD

Dr. Bradshaw received her PhD in Biochemistry from Tufts University, with a thesis exploring the DNA-binding domain of SV40. She subsequently left the field of structural biology to follow an emerging interest in immunology, joining the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital and Harvard Medical School as a research fellow in clinical immunology, and later joining the faculty. A main focus of Dr. Bradshaw’s work has been understanding the role of the human innate immune system in complex neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Interestingly, genetic studies of AD directly implicate the involvement of the innate immune system. In PD, the genetic modulation of the immune system is still being uncovered. Currently, as co-director of basic research in the new Center for Translational and Computational Neuro-immunology, led by new Division of Neuro-immunology Chief Dr. Philip De Jager, one of Dr. Bradshaw’s major research interests is the translation of findings from these studies to molecular outcomes and potentially therapeutically targetable molecules in innate immune cells.

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 phenotypes2,3,4, 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 rs3865444CC risk genotype have increased expression of CD33 on the surface of their monocytes compared to those with the rs3865444AA 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 rs3865444CC risk genotype actually only have increased expression of full-length CD33, the isoform containing the sialic acid binding domain, compared to those with the rs3865444AA 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.

Departmental Appointments

  • Department of Neurology

NIH Grants

  • MULTI-OMICNETWORK-DIRECTED PROTEOFORM DISCOVERY, DISSECTION AND FUNCTIONAL VALIDATION TO PRIORITIZE NOVEL AD THERAPEUTIC TARGETS (Federal Gov)

    Sep 30 2018 - Aug 31 2023

    DIFFERENTIAL NEURONAL SUSCEPTIBILITY AS AN AVENUE TOWARD DISEASE-MODIFYING THERAPY FOR PARKINSON (Private)

    Jul 1 2019 - Jun 30 2023

    CONVERGENCE OF MYELOID SUSCEPTIBILITY PROTEIN FUNCTION IN ALZHEIMER S DISEASE (Federal Gov)

    Apr 15 2018 - Mar 31 2023

    CONVERGENCE OF MYELOID SUSCEPTIBILITY PROTEIN FUNCTION IN ALZHEIMER S DISEASE (Federal Gov)

    Apr 15 2018 - Jan 31 2023

    CREATING AND DEPLOYING A TOOLKIT FOR HUMAN MICROGLIA IN NEURODEGENERATION (Private)

    Dec 1 2018 - Nov 30 2021

    PATHWAYDISCOVERY, VALIDATION AND COMPOUND IDENTIFICATION FOR ALZHEIMER S DISEASE (Federal Gov)

    Sep 20 2013 - Aug 31 2020

    BUILDING NOVEL PREDICTIVE NETWORKS FOR HIGH- THROUGHPUT IN-SILICO KEY DRIVER PRIORITIZATION TO ENHANCE DRUG TARGET DISCOVERY IN AMP-AD AND M2OVE-AD (Federal Gov)

    Jul 1 2018 - Jun 30 2020

    IDENTIFYING,VALIDATING AND TARGETING AD SUSCEPTIBILITY NETWORKS IN MONOCYTES (Federal Gov)

    May 1 2018 - Apr 30 2020

    MODULATION OF CD33 AS A POTENTIAL THERAPEUTIC TARGET (Private)

    Dec 8 2017 - Dec 7 2019

    INFLUENCE OF GENOTYPE ON MICROGLIA PHENOTYPE AND FUNCTION IN PD (Federal Gov)

    Jul 1 2017 - Jun 30 2019

    INFLUENCE OF GENOTYPE ON MICROGLIA PHENOTYPE AND FUNCTION IN PD (Federal Gov)

    Jul 1 2017 - Jun 30 2019

    GENETICS,FUNCTION AND SMALL MOLECULES: TARGETING THE CD33 AD LOCUS (Private)

    Jul 1 2017 - Aug 31 2018

Publications

Selected Publications
  1. Olah M, Patrick E, Villani CA, Xu J, Ryan K, Nejad P, Cimpean M, Petyuk V, Piehowski P, White C, Connor S, Yung C, Elyaman W, Schneider JA, Bennett DA, De Jager PL*, Bradshaw EM*. A transcriptomic atlas of aged human microglia informs neurodegenerative disease studies. Nat Commun. 2018 Feb 7:9(1):539.
  2. Ryan KJ, White CC, Patel K, Xu J, Olah M, Replogle JM, Frangieh M, Cimpean M, Winn P, McHenry A, Kaskow BJ, Chan G, Cuerdon N, Bennett DA, Boyd JD, Imitola J, Elyaman W, De Jager PL, Bradshaw EM. Context-specific effects of neurodegenerative disease variants in a model of human microglia. Sci Transl Med. 2017 Dec 20;9(421).
  3. Chan G, White CC, Winn PA, Cimpean M, Replogle JM, Glick LR, Cuerdon NE, Ryan KJ, Johnson KA, Schneider JA, Bennettt DA, Chibnik LB, Sperling RA, Bradshaw EM*. De Jager PL*. Modulation of TREM2 by CD33: a protein QTL study integrates Alzheimer loci in human monocytes. Nature Neuroscience. 2015 Nov;18(11):1556-8 *Co-last
  4. Bradshaw EM, Chibnik LB, Keenan BT, Ottoboni L, Raj, T, Tang A, Rosenkrantz LL, Imboywa S, Lee M, Von Korff A, The Alzheimer’s Disease Neuroimaging Initiative, Morris MC, Evans DA, Johnson K, Sperling RA, ScheniderJA, Bennett DA, De Jager PL. CD33 Alzheimer’s disease locus: Altered monocyte function and amyloid biology. Nature Neuroscience. 2013 Jul;16(7):848-50
  5. Raj T, Ryan KJ, Replogle JM, Chibnik LB, Rosenkrantz L, Tang A, Rothamel K, Stranger BE, Bennett DA, Evans DA, De Jager PL*, Bradshaw EM*. CD33: increased inclusion of exon 2 implicates the lg V-set domain in Alzheimer’s disease susceptibility. Hum Mol Genet. 2014 May 15;23(10):2729-36*Co-last