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-β (Aβ) peptides. In vitro, the "Arctic" mutation (AβE22G) accelerated Aβ fibrillization but decreased the abundance of nonfibrillar Aβ assemblies, compared with wild-type Aβ. In human amyloid precursor protein (hAPP) transgenic mice carrying mutations adjacent to Aβ that increase Aβ production, addition of the Arctic mutation markedly enhanced the formation of neuritic amyloid plaques but reduced the relative abundance of a specific nonfibrillar Aβ assembly (Aβ*56). Mice overexpressing Arctic mutant or wild-type Aβ had similar behavioral and neuronal deficits when they were matched for Aβ*56 levels but had vastly different plaque loads. Thus, Aβ*56 is a likelier determinant of functional deficits in hAPP mice than fibrillar Aβ deposits. Therapeutic interventions that reduce Aβ fibrils at the cost of augmenting nonfibrillar Aβ assemblies could be harmful.