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| David Teplow, David Geffen School of Medicine at UCLA |
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Dr. David B. Teplow is a Professor in Residence in the Department of Neurology at the David Geffen School of Medicine at UCLA and Director of the Biopolymer Laboratory at UCLA. Professor 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. Dr.Teplow's graduate work, which involved protein chemical studies of cell surface receptors, led him to Caltech in Pasadena, where he worked 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. One of the earliest applications of "microchemical methods" was in studies of the prion protein. From 1991- 2004, Dr. Teplow was a member of the Department of Neurology at Harvard Medical School, where he established a research program to understand the structural biology of the amyloid beta-protein (Abeta) and its contribution to the pathogenesis of Alzheimer's disease (AD).
Dr. Teplow is a leader in the areas of the structural biology of amyloid proteins and the biophysics of amyloid assembly. In addition to his work on Abeta assembly, Dr. Teplow has produced seminal papers in a variety of areas, including prion biology. Dr. Teplow has published ca. 130 peer-reviewed articles, including ca. 100 original articles and ca. 30 reviews, book chapters, and editorials. 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, and The Yemeni Journal of Science.
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Amyloid beta-protein oligomerization and Alzheimer's disease
David B. Teplow, Department of Neurology, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South (Room 445), Los Angeles, CA 90095-7334, USA
A seminal etiologic component of many neurodegenerative diseases is the abnormal folding and assembly of proteins. This process produces a variety of monomeric, oligomeric, and polymeric structures. In Alzheimer's disease (AD), work by anatomists in the 19th century first implicated amyloid fibrils in disease causation. Amyloid fibrils are protein homopolymers with large aspect ratios, diameters of ca. 10 nm, and common core structural organization. Amyloid fibrils also form in other neurodegenerative diseases, including the transmissible spongiform encephalopathies, Parkinson's disease, amyotrophic lateral sclerosis, and familial amyloid polyneuropathy. The wide occurrence and obvious clinical linkage of amyloid formation to neurodegeneration has stimulated intense study of amyloidogenesis. The amyloid hypothesis, which argues the primacy of amyloid fibrils in the neuropathogenesis of AD, was one of the first results of these investigations. However, a broad and increasingly compelling body of recent work now supports a revision of the hypothesis. Specifically, the primacy of fibrils in AD pathogenesis has been supplanted by the primacy of low-order oligomers.
In AD, fibrils are formed by the amyloid beta-protein (Abeta). Understanding, in molecular detail, the folding and oligomerization of the Abeta monomer has been complicated by the facts that the peptide has no stable native fold, displays a complex folding topography, and populates biologically-relevant conformational states transitorily. Nevertheless, new experimental and computational approaches have provided the means to identify and characterize novel assembly intermediates, including short, flexible, fibril-like polymers termed "protofibrils" and small pentamer/hexamer units termed "paranuclei. "Protofibrils are neurotoxic and their formation appears to be a general feature of the assembly of many different amyloidogenic proteins. Paranuclei-like assemblies have been found in AD patients and may be the proximate neurotoxins in AD. I will discuss recent results of studies of Abeta folding and assembly and the implications for understanding and treating AD.
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