Research Abstract:
There are two major areas of focus currently in my lab. Abundant evidence suggests a central role for the amyloid-b (Ab) peptide in Alzheimer's disease (AD) pathogenesis. Changes in Ab 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 particularly interested in understanding the role of endogenous (e.g. apoE) and exogenous Ab binding molecules (anti-Ab antibodies) in regulating Ab 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. Ab brain microdialysis) to study mechanisms leading to AD and cerebral amyloid anigopathy (CAA). In addition, in recent studies, we have been attempting to develop antecedent biomarkers for AD via assessing CSF and plasma samples from human subjects at the Washington University ADRC. We are utilizing mass spectrometry and other proteomic approaches.
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:
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.
Brendza RP, Bacskai BJ, Cirrito JR, et al. Anti-ABeta antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice. J Clin Invest 2005 115:428-433.
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.
DeMattos RB, Cirrito JR, Parsadanian M, et al. ApoE and clusterin cooperatively suppress ABeta levels and deposition: Evidence that apoE regulates extracellular ABeta metabolism in vivo. Neuron 2004 41:193-202.
DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM. Brain to plasma amyloid-Beta efflux: A measure of brain amyloid burden in a mouse model of Alzheimer's disease. Science 2002 295:2264-2267.
Last Updated: 01/23/2007 |