Research Abstract:
There are two major areas of focus currently in my lab. Abundant evidence suggests a central role for the amyloid-beta (Abeta) peptide in Alzheimer's disease (AD) pathogenesis. Changes in Abeta 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 Abeta metabolism in the CNS. Some of our studies are trying to understand the role of endogenous (e.g. apoE) and exogenous Abeta binding molecules (anti-Abeta antibodies) in regulating Abeta 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. Abeta 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 Abeta metabolism is synaptic activity. We have found that synaptic activity and synaptic vesicle release is coupled with Abeta release from the synapse in vivo. This finding has important implications for understanding why Abeta deposition occurs in specific brain regions as well as has important implications for development of novel treatments. 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 Abeta42 and increased tau 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.
Selected Publications:
Brody DL, Magnoni S, Schwetye KE, Spinner M, Esparza TJ, Stocchetti N, Zipfel GJ, Holtzman DM. Amyloid-b dynamics correlate with neurological status in the injured human brain. Science 2008 321:1221-1224.
Cirrito JR, Kang J-E, Lee J, Stewart FR, Verges D, Silverio LM, Bu G, Mennerick S, Holtzman DM. Endocytosis is required for synaptic activity-dependent release of amyloid-b in vivo. Neuron 2008 58:42-51.
Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen, Wellington CL, Bales KR, Paul SM, Holtzman DM. Over-expression of ABCA1 in the PDAPP mouse model of Alzheimer's disease markedly reduces amyloid deposition. J. Clin. Invest. 2008 188:671-682.
Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nature Medicine 2006 12:856-861.
Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 2005 48:913-922.
Last Updated: 08/27/2009 |