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David M. Holtzman, MD

Dr. Holtzman is the Andrew B. and Gretchen P. Jones Professor and Chairman of Neurology, Professor of Developmental Biology, Associate Director of the Alzheimer's Disease Research Center, and a member of the Hope Center for Neurological Disorders.

A major interest in my lab is in understanding basic mechanisms underlying acute and chronic cell dysfunction in the CNS particularly as these mechanisms may relate to Alzheimer's disease (AD) and injury to the developing brain.

There are two major areas of focus currently in my lab. Abundant evidence suggests a central role for the amyloid-β (Aβ) peptide in Alzheimer's disease (AD) pathogenesis. Changes in Aβ conformation from forms with predominantly random coil/alpha helix to both soluble and insoluble forms with high beta-sheet content appears to be a key event in AD. We are interested in developing a better understanding of Aβ metabolism in the CNS. Some of our studies are trying to understand the role of endogenous (e.g. apoE) and exogenous Aβ binding molecules (anti-Aβ antibodies) in regulating Aβ metabolism and toxicity. ApoE genotype is the most important genetic risk factor for AD and understanding how it contributes to AD pathogenesis is likely to provide key insights into the cause of and potentially treatments for AD. We use a variety of transgenic and knockout mice as well as unique biological assays (e.g. Aβ brain microdialysis) to study mechanisms leading to AD pathology and cerebral amyloid angiopathy (CAA). Over the past several years, we have found that another major regulator of Aβ metabolism is synaptic activity. We have found that synaptic activity and synaptic vesicle release is coupled with Aβ release from the synapse in vivo. This finding has important implications for understanding why Aβ deposition occurs in specific brain regions as well as has important implications for development of novel treatments. In addition to studies on Aβ and apoE metabolism, we have also been studying the metabolism of tau protein. Specifically, we have been able to assess extracellular tau by in vivo microdialysis and are interested in understanding the regulation of tau metabolism and how to block tau aggregation and its spread within the CNS. In human studies, it has been shown that by the time of clinical onset of AD, there is already substantial buildup of amyloid in the brain along with neurofibrillary pathology, neuronal cell death, and synaptic loss. It is estimated that AD pathology begins to build up ~10-15 years prior to onset of dementia. Thus, a major goal in the field is to discover antecedent biomarkers for AD to detect AD pathology prior to symptom onset so that treatments can be used to prevent and delay dementia. We have been assessing CSF and plasma samples from human subjects at the Washington University ADRC and have found that decreased CSF Aβ42 and increased tau, VILIP-1, and YKL-40 are harbingers of cognitive decline in cognitively normal elderly. We are following up on these findings as well as utilizing traditional methods such as ELISA as well as mass spectrometry coupled with neuroimaging to find new biomarkers.

Hypoxic-ischemic (H-I) injury to the neonatal brain is a frequent cause of encephalopathy, seizures, and motor impairment (cerebral palsy). Our lab is interested in further understanding molecular mechanisms of brain injury following neonatal H-I as well as developing potential treatments to prevent or limit brain injury. We have found that certain agents are particularly protective against H-I induced injury in neonatal animals and are in the process of exploring the cellular and molecular pathways that underlie these effects.

Medical Training

Dr. Holtzman attended the Honors Program in Medical Education at Northwestern University receiving his B.S. (1983) and M.D. (1985). He did medical internship followed by Neurology residency at UCSF from 1985-1989. He then did post-doctoral research training in the lab of William C. Mobley, MD, PhD, at UCSF from 1989-1994. At UCSF, he also established the Memory and Cognitive Disorders Clinic and was an Assistant Professor from 1991-1994. He moved to his own laboratory at Washington University in December of 1994. He was named as the Associate Professor of Neurology in 2001, Professor in November of 2002, and as the Andrew and Gretchen Jones Professor and head of the Department of Neurology in October 2003. In addition to his laboratory, administrative, and teaching duties, Dr. Holtzman is involved in clinical and research activities at the Washington University Alzheimer's Disease Research Center. Past honors include being the recipient of a Paul Beeson Physician Faculty Scholar Award in Aging Research, recipieint of the Potamkin Prize from the American Academy of Neurology for research on Alzheimer's (2003), election to the American Society for Clinical Investigation (2004), receiving a MERIT award from the NIA (2004), being a recipient of the MetLife award on Alzheimer's disease (2006), election to the Institute of Medicine of the National Academy of Sciences (2008), being a recipient of the alumni merit award from Northwestern Feinberg School of Medicine (2010), being appointed to the National Advisory Council of the NINDS (2011), a recipient of the Chancellor’s Award for Innovation and Entrepreneurship (2013), and being elected Fellow of the AAAS (2014).

Selected Publications

For a recent list of Dr. Holtzman's publications, please visit the Holtzman Publications page.

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