Cellular/Molecular/Biomarkers studies of Alzheimer's disease and neonatal brain injury.

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.