Research Abstract:
The pathophysiology of Alzheimer disease and pharmacodynamic measurements of disease-modifying treatments. Our laboratory’s focus is on the causes, diagnosis and future treatments of Alzheimer disease. We directly measure the pathophysiology of Alzheimer disease in humans using multiple techniques and also perform in vitro cell culture experiments.
Our group uses a wide variety of assays and techniques from the most basic applications, such as quantitative measurement of stable-isotope labeled peptides to clinical translational studies in diagnostic and therapeutic biomarkers for Alzheimer’s disease. We have several ongoing studies including:
1) In Vivo metabolism of Aβ in Alzheimer's Disease: We have pioneered a new technique to measure amyloid-beta metabolism in humans. Ongoing studies in Alzheimer’s disease and controls will address the hypothesis that there is a change in amyloid-beta metabolism in people who develop Alzheimer's disease compared to people who do not.
2) Familial Adult Children Study: We are investigating the changes that occur in autosomal dominant Alzheimer disease; including structural changes by MRI, pathological changes by PET-PIB, functional changes by Clinical Dementia Rating and neuropsychometric testing, and pathophysiological changes in CSF biomarkers and CNS protein production and clearance rates.
3) Pharmacodynamic response of proposed disease modifying therapies for Alzheimer disease are tested by directly measuring the production, clearance and steady-state levels of the targeted proteins, including amyloid-beta. These studies quantitate targeted activity of therapeutics and provide evidence that these compounds are effective in humans.
4) CNS derived proteomics and measurements: We are currently investigating multiple other CNS derived proteins and are developing methods to measure hundreds of protein metabolism profiles in humans using highly sensitive nano-flow mass spectrometry and in vivo labeling techniques. Advanced bio-informatics, cutting edge mass spectrometry, and in vivo and in vitro labeling experiments are used for highly quantitative analysis of proteins.
Selected Publications:
Bateman RJ, Munsell LY, Chen X, Holtzman DM, Yarasheski KE. Stable Isotope Labeling Tandem Mass Spectrometry (SILT) to Quantify Protein Production and Clearance Rates. Journal of the American Society for Mass Spectrometry 2007.
Bateman RJ, Wen G, Morris JC, Holtzman DM. Fluctuations of CSF amyloid-{beta} levels: Implications for a diagnostic and therapeutic biomarker. Neurology 2007 68(109).
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. Nat Med 2006 12(7).
Yan P, Hu X, Song H, Yin K, Bateman RJ, Cirrito JR, Xiao Q, Hsu FF, Turk JW, Xu J, Hsu CY, Holtzman DM, Lee JM. Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J Biol Chem 2006.
Yin K-J, Cirrito JR, Yan P, Hu X, Xiao Q, Pan X, Bateman R, Song H, Hsu F-F, Turk J, Xu J, Hsu CY, Mills JC, Holtzman DM, Lee J-M. Matrix Metalloproteinases Expressed by Astrocytes Mediate Extracellular Amyloid-beta Peptide Catabolism. J Neurosci 2006 26(43).
Last Updated: 08/04/2008 |