Accelerating amyloid-β fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models

Many proteins suspected of causing neurodegenerative diseases exist in diverse assembly states. For most, it is unclear whether shifts from one state to another would be helpful or harmful. We used mutagenesis to change the assembly state of Alzheimer disease (AD)-associated amyloid-beta (A beta) peptides. In vitro, the Arctic mutation (A beta E22G) accelerated A beta fibrillization but decreased the abundance of nonfibrillar A beta assemblies, compared with wild-type A beta. In human amyloid precursor protein (hAPP) transgenic mice carrying mutations adjacent to A beta that increase A beta production, addition of the Arctic mutation markedly enhanced the formation of neuritic amyloid plaques but reduced the relative abundance of a specific nonfibrillar A beta assembly (A beta*56). Mice overexpressing Arctic mutant or wildtype A beta had similar behavioral and neuronal deficits when they were matched for A beta*56 levels but had vastly different plaque loads. Thus, A beta*56 is a likelier determinant of functional deficits in hAPP mice than fibrillar A beta deposits. Therapeutic interventions that reduce A beta fibrils at the cost of augmenting nonfibrillar A beta assemblies could be harmful.