Amyloid-? Protofibril Formation and Neurotoxicity Implications for Alzheimer’s Disease

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia. A characteristic feature of AD is the presence of amyloid plaques in the cortex and hippocampus of the brain. The principal component of these plaques is the amyloid-? (A?) peptide, a cleavage product from proteolytic processing of amyloid precursor protein (APP). A central event in AD pathogenesis is the ability of A? monomers to aggregate into amyloid fibrils. This process involves the formation of various A? intermediates, including protofibrils. Protofibrils have been implicated in familial AD, as the Arctic APP mutation is associated with enhanced rate of protofibril formation in vitro.This thesis focuses on A? aggregation and neurotoxicity in vitro, with special emphasis on protofibril formation. Using synthetic A? peptides with and without the Arctic mutation, we demonstrated that the Arctic mutation accelerated both A?1-42 protofibril- and fibril formation, and that these processes were affected by changes in the physiochemical environment.Oxidation of A? methionine delayed trimer and protofibril formation in vitro. Interestingly, these oxidized peptides did not have the neurotoxic potential of their un-oxidized counterparts, suggesting that formation of trimers and further aggregation into protofibrils is necessary for the neurotoxic actions of A?. In agreement, stabilization of A? wild type protofibrils with the omega-3 (?3) fatty acid docosahexaenoic acid (DHA) sustained A? induced neurotoxicity; whereas in absence of DHA, neurotoxicity was reduced as A? fibrils were formed. These results suggest that the neurotoxic potential of A? is mainly confined to soluble aggregated forms of A?, not A? monomer/dimers or fibrillar A?.Stabilization of A? protofibrils with DHA might seem contradictory, as ?3 fatty acids generally are considered beneficial for cognition. However, we also demonstrated that DHA supplementation reduced A? levels in cell models of AD, providing a possible mechanism for the reported beneficial effects of DHA on cognitive measures in vivo.