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 scientific director of the Hope Center for Neurological Disorders.
My lab is interested in understanding the pathogenesis of Alzheimer’s disease and other neurodegenerative disorders. 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. brain microdialysis to measure proteins and other metabolites) to study mechanisms leading to AD pathology and cerebral amyloid angiopathy (CAA). Over the past several years, we have found that a 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. It is also likely relevant to how the sleep/wake cycle regulates Aβ levels and deposition. We are actively pursuing the relationship between sleep and neurodegenerative disease. Interestingly, there is an increased risk of AD in individuals with high glucose and diabetes. We are following up this link by study whether changes in glucose and insulin acutely and chronically impact on AD-related protein metabolism in the brain. 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, neurogranin, 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.
For a recent list of Dr. Holtzman’s Publications, please visit the Holtzman Publications page.