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Biophysical Studies of the Initial Oligomerization Events in Amyloid b-Protein Assembly

Gal Bitan†, Aleksey Lomakin‡, Tomas T. Ding†, Marina D. Kirkitadze†, Peter T. Lansbury†, George B. Benedek‡, and David B. Teplow†

David Teplow (left) and Gal Bitan (right)	View Gal Bitan's presentation

Abstract: Soluble oligomers of the amyloid b-protein (Ab) are neurotoxic and have been shown to cause neuronal dysfunction in the absence of fibril formation. In particular, oligomers of Ab(1-42) have been implicated as neurotoxic effectors involved in early stages of Alzheimer's disease (AD). Understanding the formation of Ab oligomers and their role in the pathogenesis of AD is thus of clinical importance. Biophysical characterization of small Ab oligomers has been difficult due to the metastable nature of these assemblies. However, through the use of a technique termed Photo-Induced Cross-linking of Unmodified Protein (PICUP), we recently were able to demonstrate that low molecular weight (LMW) Ab(1-40) exists as a mixture of small oligomers in rapid equilibrium. Here, PICUP, dynamic light scattering (DLS), atomic force microscopy (AFM), and circular dichroism (CD) have been used in combination to study the oligomerization of LMW Ab(1-40) and Ab(1-42). Although no ordered secondary structure is detectable at early assembly stages, oligomers of both alloforms form immediately following isolation of LMW Ab. LMW Ab(1-40) comprises monomer, dimer, trimer, and tetramer, in rapid equilibrium, whereas LMW Ab(1-42) forms larger assemblies in which hexamers appear to be the "unit cells." Systematic study of Ab alloforms ranging in length from 40-43 amino acids revealed a direct correlation between Ab length and the oligomer size distribution. The analytical strategy used here should be of value for the study of other abnormal, and normal, protein oligomerization processes.

†Center for Neurologic Diseases, Brigham and Women's Hospital, and Department of Neurology, Harvard Medical School, Boston, MA 02115; ‡Department of Physics, Center for Material Science and Engineering, and Materials Processing Center, Massachusetts Institute of Technology, Cambridge, MA 02139

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