Amyloid fibrils and other ordered aggregation products of the Alzheimer's plaque peptide A-beta have been implicated by genetic, pathological, and cell culture studies to have a role in the development of Alzheimer's disease. Strategies targeting the growth or toxicity of these aggregates are formally possible but technically difficult owing in part to our ignorance of both fibril structure and of fibril assembly pathways and energetics. In this grant application we propose to implement new strategies to obtain information on structure and assembly, which will contribute, for example, to both the design and testing of inhibitors of fibril formation. We will utilize scanning mutagenesis linked to a number of in vitro assays for fibril growth to dissect the roles of key amino acid residue positions of A-beta in fibril formation and stability. We will use surface plasmon resonance (SPR) to study details of the kinetics of fibril assembly and disassembly with both wild type and mutant A-beta sequences.
| Chemuru, Saketh; Kodali, Ravindra; Wetzel, Ronald (2016) C-Terminal Threonine Reduces A?43 Amyloidogenicity Compared with A?42. J Mol Biol 428:274-291 |
| Misra, Pinaki; Kodali, Ravindra; Chemuru, Saketh et al. (2016) Rapid ?-oligomer formation mediated by the A? C terminus initiates an amyloid assembly pathway. Nat Commun 7:12419 |
| Chemuru, Saketh; Kodali, Ravindra; Wetzel, Ronald (2014) Improved chemical synthesis of hydrophobic A? peptides using addition of C-terminal lysines later removed by carboxypeptidase B. Biopolymers 102:206-21 |
| Kodali, Ravindra; Williams, Angela D; Chemuru, Saketh et al. (2010) Abeta(1-40) forms five distinct amyloid structures whose beta-sheet contents and fibril stabilities are correlated. J Mol Biol 401:503-17 |
| Gardberg, Anna; Dice, Lezlee; Pridgen, Kathleen et al. (2009) Structures of Abeta-related peptide--monoclonal antibody complexes. Biochemistry 48:5210-7 |
| Wetzel, Ronald; Shivaprasad, Shankaramma; Williams, Angela D (2007) Plasticity of amyloid fibrils. Biochemistry 46:1-10 |
| Gardberg, Anna S; Dice, Lezlee T; Ou, Susan et al. (2007) Molecular basis for passive immunotherapy of Alzheimer's disease. Proc Natl Acad Sci U S A 104:15659-64 |
| Kodali, Ravindra; Wetzel, Ronald (2007) Polymorphism in the intermediates and products of amyloid assembly. Curr Opin Struct Biol 17:48-57 |
| Williams, Angela D; Shivaprasad, Shankaramma; Wetzel, Ronald (2006) Alanine scanning mutagenesis of Abeta(1-40) amyloid fibril stability. J Mol Biol 357:1283-94 |
| Shivaprasad, Shankaramma; Wetzel, Ronald (2006) Analysis of amyloid fibril structure by scanning cysteine mutagenesis. Methods Enzymol 413:182-98 |
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