Comparison of neurotoxicity of different aggregated forms of Aβ40, Aβ42 and Aβ43 in cell cultures

The abnormal deposition of amyloid-beta(A beta) peptides in the brain is the main neuropathological hallmark of Alzheimer's disease (AD). Amyloid deposits are formed by a heterogeneous mixture of A beta peptides, among which the most studied are A beta 40 and A beta 42. A beta 40 is abundantly produced in the human brain, but the level of A beta 42 is remarkably increased in the brain of AD patients. Aside from A beta 40 and A beta 42, recent data have raised the possibility that A beta 43 peptides may be instrumental in AD pathogenesis. Besides its length, whether the A beta aggregated form accounts for the neurotoxicity is also particularly controversial. A beta fibrils are generally considered as key pathogenic substances in AD pathogenesis. Nevertheless, recent data implicated soluble A beta oligomers as the main cause of synaptic dysfunction and memory loss in AD. To further address this uncertainty, we analyzed the neurotoxicity of different A beta species and A beta forms at the cellular level. The results showed that A beta 42 could form oligomers significantly faster than A beta 40 and A beta 43 and A beta 42 oligomers showed the greatest level of neurotoxicity. Regardless of the length of A beta peptides, A beta oligomers induced significantly higher cytotoxicity compared with the other two A beta forms. Surprisingly, the neurotoxicity of fibrils in PC12 cells was only marginally but not significantly stronger than monomers, contrary to previous reports. Altogether, our findings demonstrate the high pathogenicity of A beta 42 among the three Aa species and support the idea that A beta 42 oligomers contribute to the pathological events leading to neurodegeneration in AD. Copyright (C) 2017 European Peptide Society and John Wiley & Sons, Ltd.