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 beta-protein (A beta) fibrillogenesis are neurotoxic. We studied early aggregation assemblies of wild-type and mutant A beta bearing the E22G (Arctic) familial Alzheimer's disease mutation. Using a novel method to present purified, disaggregated A beta peptides to primary cortical neurons, the detailed temporal pattern of neurotoxicity was assessed Neurons exposed to Arctic A beta showed a progressive degeneration that was much more rapid than that with wild-type A beta, 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 A beta oligomers, which were followed by a time-dependent elongation of curvilinear A beta 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 A beta 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. (c) 2005 Elsevier Inc. All rights reserved.