Different conformations of amyloid β induce neurotoxicity by distinct mechanisms in human cortical neurons

Characterization of soluble oligomeric amyloid beta( A beta) species in the brains of Alzheimer's disease ( AD) patients and transgenic models has raised the possibility that different conformations of A beta may contribute to AD pathology via different mechanisms. To characterize the toxic effect of different A beta conformations, we tested side by side the effect of well characterized A beta oligomers ( A beta Os), A beta-derived diffusible ligands ( ADDLs), and fibrillar A beta( A beta f) preparations in human cortical neurons ( HCNs). Both A beta Os and ADDLs bind rapidly and with high affinity to synaptic contacts and cellular membranes. A beta Os ( 5 mu M) induced rapid and massive neuronal death. Calcium influx accelerated, but was not required for, A beta O toxicity. A beta Os elicited a stereotyped succession of cellular changes consistent with the activation of a mitochondrial death apoptotic pathway. At low concentrations A beta Os caused chronic and subtler mitochondrial alterations but minimal cell death. ADDLs induced similar toxic changes as A beta Os but on a fivefold longer time scale. Higher concentrations of A beta f and longer incubation times were required to produce widespread neuritic dystrophy but modest HCN cell death. Thus various A beta species may play relevant roles in AD, causing neurotoxicity by distinct non-overlapping mechanisms affecting neuronal function and viability over multiple time courses.