Small non-fibrillar assemblies of amyloid β-protein bearing the Arctic mutation induce rapid neuritic degeneration

Recent studies suggest that soluble intermediates formed during amyloid β-protein (Aβ) fibrillogenesis are neurotoxic. We studied early aggregation assemblies of wild-type and mutant Aβ bearing the E22G (“Arctic”) familial Alzheimer's disease mutation. Using a novel method to present purified, disaggregated Aβ peptides to primary cortical neurons, the detailed temporal pattern of neurotoxicity was assessed. Neurons exposed to Arctic Aβ showed a progressive degeneration that was much more rapid than that with wild-type Aβ, beginning in dendrites and axons and leading to frank cell death. This neurotoxicity paralleled the aggregation process, with neuritic injury first appearing in the presence of small spherical Aβ oligomers, which were followed by a time-dependent elongation of curvilinear Aβ assemblies. One of the earliest neuritic changes was the formation of neurofilament-positive ringlets within axons, which disappeared as neurites followed by cell body degeneration. Our data support the hypothesis that small Aβ intermediates formed early in the aggregation process initiate cellular dysfunction beginning in neurites, leading to neuronal loss. A similar pattern of degeneration may occur during the preclinical and early clinical phases of Alzheimer's disease.