David Holtzman, M.D.
Professor of NeurologyWashington University
David Holtzman is a neurologist and neuroscientist. He has focused much of his efforts over the last 27 years on trying to better understand mechanisms underlying neurodegeneration, particularly as they are relevant to Alzheimer’s disease (AD). His lab has published extensively on the neurobiology of apoE and its receptors, apoE and TREM2 effects on the innate immune system, how apoE, Aβ binding molecules, and other factors such as neuronal activity and sleep influence Aβ and tau metabolism, their accumulation, and their effects. In studying tau metabolism and tau-mediated brain injury, his lab found that apoE, particularly apoE4, strongly influences tau-mediated neurodegeneration via the brain’s innate immune response. Over the last 8 years, the lab has studied how microglia and specific microglial genes such as TREM2 as well as apoE (produced by astrocytes and microglia) influence neurodegeneration in the setting of Aβ and tau pathology as well as Aβ-induced tau seeding/spreading. From the therapeutic perspective, the lab has shown that certain anti-Aβ, anti-tau and anti-apoE antibodies have therapeutic potential in animal models. The use of one of the anti-Aβ antibodies that was studied for potential therapeutic and diagnostic purposes was licensed by Washington University (WU) to Eli Lilly in 2001 and subsequently humanized. It is in a secondary prevention trial in preclinical AD (A4). The lab also developed an anti-apoE antibody (HAE-4) that only binds non-lipidated apoE that clears amyloid plaques and decreases CAA and CAA-associated vascular dysfunction. It is being developed for clinical trials. The lab has developed 2 techniques to allow us to better study metabolism of Aβ, tau, apoE, and other proteins in the CNS including: a protein microdialysis method used to assess proteins as frequently as every 30 minutes in the brain interstitial fluid of awake rodents and humans, and a metabolic labeling technique using 13C-labeled amino acids following by sampling of human CSF or rodent brain to measure rates of protein synthesis and clearance in the CNS. In humans, the lab worked extensively on the development of antecedent biomarkers of AD. In his 27 years at WU, Dr. Holtzman has trained/ mentored ~70 graduate students, postdoctoral fellows, and physician-scientists, many who are in successful careers in academia and industry. These include Anne Fagan, PhD, John Cirrito, PhD, John Fryer, PhD, Randall Bateman, MD, David Brody, MD, PhD, Greg Zipfel, MD, Tim Miller, MD, PhD, Jungsu Kim, PhD, Miranda Lim, MD, PhD, Erik Musiek, MD, PhD, Yo-El Ju, MD, Joseph Castellano, PhD, and Gus Davis, MD, PhD all of whom have gone on to successful independent careers in academia as well as Ron DeMattos, PhD, Helen Hu, PhD, Phillip Verghese, PhD, Tim West, PhD, Adam Bero, PhD, Kiran Yanamandra, PhD, Fan Liao, PhD, Jerrah Holth, PhD, Cheryl Leyns, PhD, and Monica Xiong, PhD who have gone on to successful careers in industry.