David Holtzman, MD

Cellular/Molecular/ Biomarker studies of Alzheimer’s Disease and neonatal brain injury

Dr. Holtzman is the Barbara Burton and Reuben M. Morriss III Distinguished Professor, 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, the effects of the sleep/wake cycle on Aβ metabolism, as well as has important implications for development of novel treatments.

Following up our work on the effects of sleep on Aβ metabolism, we are also assessing the effects of Aβ aggregation in the brain on sleep as well as the effects of other neurodegenerative pathologies on sleep. 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.