David Holtzman is a neurologist and neuroscientist. The Holtzman lab has focused much of its efforts over the last thirty years on trying to better understand mechanisms underlying neurodegeneration, particularly as they are relevant to Alzheimer’s disease (AD). The lab has published extensively on the neurobiology of apoE and its receptors, apoE and TREM2 and their effects on the innate and adaptive 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, we found that apoE, particularly apoE4, strongly influences tau-mediated neurodegeneration via the brain’s innate and adaptive immune response. Over the last eleven years, we studied how microglia and specific microglial genes such as TREM2 as well as apoE (produced at high levels by astrocytes and reactive microglia) influence neurodegeneration in the setting of Aβ and tau pathology as well as Aβ-induced tau seeding/spreading. From the therapeutic perspective, we have shown that certain anti-Aβ, anti-tau, and anti-apoE antibodies have therapeutic potential in animal models. We developed an anti-apoE antibody (HAE-4) that only binds non-lipidated apoE that appears to be present only in amyloid plaques. HAE-4 clears both plaques and CAA and improves CAA-associated vascular dysfunction. It is being developed for clinical trials. We have developed two 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. This technology, along with antibodies developed in my lab, further studied by the Bateman lab, has led to the development of novel plasma biomarkers of AD pathology. In humans, we worked extensively on the development of antecedent biomarkers of AD.
In my 30 years at WashU, I trained/ mentored over 70 graduate students, postdoctoral fellows, and physician-scientists, many who are in successful careers in academia and industry. These include Randall Bateman, MD, John Cirrito, PhD, John Fryer, PhD, 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, Jason Ulrich, PhD, Gus Davis, MD, PhD, Gilbert Gallardo, PhD, Yang Shi, PhD, Chao Wang, PhD and Maud Gratuze, 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, Fan Liao, PhD, Jerrah Holth, PhD, Cheryl Leyns, PhD, Sarah Frischi, PhD, Monica Xiong, PhD, and Chanung Wang, who have gone on to successful careers in industry.