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| Degree: |
Ph.D., University of Washington
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| Laboratory Address: |
635 Charles E. Young Drive South
Los Angeles, CA 90095
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| Office Address: |
NRB 445
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310-206-1700
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Work Phone Number:
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310-206-2030
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Biology and biochemistry of human neurodegenerative diseases
The Teplow laboratory seeks to understand and treat neurodegenerative disorders linked to aberrant protein folding and assembly. The laboratory has special expertise in Alzheimer's disease (AD), the most common cause of late-life dementia. A seminal pathogenetic effector of AD is thought to be the amyloid beta-protein (Abeta), actually a 40-42 residue peptide, that self-associates to form amyloid plaques in AD patients. Studies by our group, and those of others, has revealed that the Abeta monomer can form a variety of oligomeric and polymeric structures with potent neurotoxic activities. Oligomeric structures, which have been identified in vitro and found to exist in vivo in AD patients, may be the proximate neurotoxins in AD. Importantly, such oligomers are being identified in an increasing number of amyloid diseases, suggesting the existence of a common pathogenetic pathway.
Our research strategy is interdisciplinary. We employ in vivo, in vitro, in vacuo, and in silico approaches to understand how the nascent Abeta monomer folds and assembles into neurotoxic oligomeric and polymeric forms. In vitro studies using AFM, EM, CD, FT-IR, intrinsic fluorescence, solution-state NMR, and in situ chemical cross-linking have revealed morphologic, conformational, and aggregation features of the assembly of synthetic Abeta. Structure-activity correlations in vivo have been made through studies of the effects of exogenous Abeta monomers and higher-order assemblies on the physiology of cultured neurons and neuronal cell lines. A powerful in vacuo method, ion mobility spectroscopy (IMS), has been used to determine the masses and collision cross sections of non-covalently-associated oligomers. IMS has been particularly valuable because of the dearth of methods available for studying the metastable, polydisperse oligomer populations that are produced by Abeta. IMS resolves ions of identical m/z, an ability vital to the analysis of homopolymers. In addition, the collision cross sections derived from IMS constrain replica-exchange molecular dynamics (MD) simulations, allowing the production of models of the three-dimensional structure of Abeta in the oligomeric assemblies. At the monomer level, and in larger systems, we also employ other in silico methods to study the conformational dynamics and assembly of Abeta. These methods involve discrete MD algorithms coupled with increasingly complex representations of amino acids (four-bead, united-atom, all-atom) to produce models of Abeta structure and insight into the conformational dynamics of Abeta assembly. Our long-term goal is to discover the key factors controlling production of neurotoxic assemblies and then to target these factors in strategies for drug development. We expect that the superb translational research capabilities at UCLA will foster the clinical testing of compounds resulting from our research efforts.
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David Teplow received B.A. degrees in Biochemistry (1974) and in Bacteriology and Immunology (1975) at the University of California at Berkeley. He did graduate work in Tumor and Molecular Immunology at the University of Washington, where he received his M.S. (1977) and Ph.D. (1981) degrees. His graduate work, which involved protein chemical studies of cell surface receptors, led him to Caltech in Pasadena, where he worked first as a postdoctoral fellow and then as a junior faculty member to develop highly sensitive methods for protein primary structure analysis and to apply these new methods to the study of proteins in the nervous system. From 1991 through 2004, Dr. Teplow was a faculty member in the Departments of Neurology at Brigham and Women's Hospital and Harvard Medical School,
where he established a research program to understand the structural biology of the amyloid β-protein (Aβ) and its contribution to the pathogenesis of Alzheimer's disease (AD). Dr. Teplow joined the faculty at UCLA in 2005, where he currently is a Professor in Residence in the Department of Neurology, a member of the Molecular Biology Institute and the Brain Research Institute, and Director of the Biopolymer Laboratory at UCLA.
Dr. Teplow is a leader in the areas of the structural biology of amyloid proteins and the biophysics of amyloid assembly. The Teplow laboratory seeks to understand and treat neurodegenerative disorders linked to pathologic protein folding. In AD, Aβ self-associates to form a variety of oligomeric and polymeric structures with potent neurotoxic activities. Aβ oligomers have been found in vivo in AD patients and may be the proximate neurotoxins in the disease. To understand how the nascent Aβ monomer folds and assembles into neurotoxic forms, Dr. Teplow has employed an interdisciplinary strategy comprising in vivo, in vitro, in vacuo, and in silico approaches. The long-term goal is to discover the key factors controlling production of neurotoxic assemblies and then to target these factors in strategies for drug development. Dr. Teplow has published ~140 peer-reviewed articles,
including ~100 original articles and ~40 reviews, book chapters, and commentaries. Dr. Teplow was a founding editorial board member of the Journal of Molecular Neuroscience and currently sits on the editorial boards of The Journal of Biological Chemistry, Amyloid: The Journal of Protein Folding
Disorders, Current Chemical Biology, and The Yemeni Journal of Science.
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Roychaudhuri R, Yang M, Hoshi MM, Teplow DB Amyloid β-protein assembly.
J Biol Chem, 284:4749–4753
2009;
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Maji Samir K, Ogorzalek Loo Rachel R, Inayathullah Mohammed, Spring Sean M, Vollers Sabrina S, Condron Margaret M, Bitan Gal, Loo Joseph A, Teplow David B Amino Acid Position-specific Contributions to Amyloid {beta}-Protein
Oligomerization..
The Journal of biological chemistry.
2009; 284(35):
23580-91.
Yang Mingfeng, Teplow David B Amyloid beta-protein monomer folding: free-energy surfaces reveal
alloform-specific differences..
Journal of molecular biology.
2008; 384(2):
450-64.
Ono Kenjiro, Condron Margaret M, Ho Lap, Wang Jun, Zhao Wei, Pasinetti Giulio M, Teplow David B Effects of grape seed-derived polyphenols on amyloid beta-protein
self-assembly and cytotoxicity..
The Journal of biological chemistry.
2008; 283(47):
32176-87.
Yamin Ghiam, Ono Kenjiro, Inayathullah Mohammed, Teplow David B Amyloid beta-protein assembly as a therapeutic target of Alzheimer's
disease..
Current pharmaceutical design.
2008; 14(30):
3231-46.
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