Different Conformations of Amyloid β Induce Neurotoxicity by Distinct Mechanisms in Human Cortical Neurons

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

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