The original model of Alzheimer's disease focused primarily on the formation of amyloid plaques in the brain as the major cause of memory loss and dementia. Recent evidence suggests that the beta-amyloid peptide (Abeta) involved in plaque formation also exists in an oligomeric form, which has demonstrated greater cytotoxicity compared to the amyloid fibrils that make up amyloid plaques. One model of toxicity involves the formation of membrane spanning pores similar to pore-forming bacterial toxins, another, chelation and reduction of Cu(ll) or Fe(lll) to produce toxic H202. The focus of this project is the characterization of the structural and conformational changes in Abeta leading to aggregation. Conformational changes preceding aggregation of oligomeric to fibrillar Abeta are elusive due to the considerable insolubility of fibrillar Abeta. A number of variants of Abeta(1-42), with reduced aggregation rates, have been developed and will be used to study the conformational changes leading to metal chelation, oligomerization and fibrillization. UV resonance Raman (UVRR), will be employed to identify structural changes in the polypeptide backbone as well as the nature of the histadine-metal binding of Abeta. Circular dichroism and dynamic light scattering will be used to complement the resonance Raman data thereby creating a comprehensive model of the oligomerization and fibrillization processes.
| JiJi, Renee D; Balakrishnan, Gurusamy; Hu, Ying et al. (2006) Intermediacy of poly(L-proline) II and beta-strand conformations in poly(L-lysine) beta-sheet formation probed by temperature-jump/UV resonance Raman spectroscopy. Biochemistry 45:34-41 |
