Understanding secondary nucleation of the amyloid β peptide

Abstract: Alzheimer’s Disease (AD) is a devastating neurodegenerative disease associated with massive neuronal cell death during its pathology. The involvement of the amyloid β 42 (Aβ42) peptideand its role in neurotoxicity is now well established. It is known that the production of oligomers during the aggregation of Aβ42 into highly ordered fibrils is responsible for neuronal cell death. However, the efforts in finding a cure have been greatly hindered because of the lack of understanding of the molecular mechanisms of Aβ42 aggregation. This thesis focuses on understanding the molecular mechanism of secondary nucleation, the process which is most prolific in the production of oligomers. In particular, the work focuses on intrinsicfactors affecting secondary nucleation such as hydrophobic residues and surfaces on the fibrils, which catalyze the aggregation of monomers during secondary nucleation. We also show the possibility of molecular specificity being involved in secondary nucleation, and open avenues of further studies that will help understand the molecular mechanism of this phenomenon.