Quaternary Structure Defines a Large Class of Amyloid-β Oligomers Neutralized by Sequestration

• Brain-derived amyloid-β oligomers (Aβo) are classified as type 1 and type 2
• Type 1 Aβo, A11-immunoreactive, have no spatiotemporal relationship with Aβ plaques
• Type 2 Aβo, OC-immunoreactive, emerge after and accumulate around Aβ plaques
• Type 2 Aβo, despite being highly abundant, do not impair cognition in situ

SummaryThe accumulation of amyloid-β (Aβ) as amyloid fibrils and toxic oligomers is an important step in the development of Alzheimer’s disease (AD). However, there are numerous potentially toxic oligomers and little is known about their neurological effects when generated in the living brain. Here we show that Aβ oligomers can be assigned to one of at least two classes (type 1 and type 2) based on their temporal, spatial, and structural relationships to amyloid fibrils. The type 2 oligomers are related to amyloid fibrils and represent the majority of oligomers generated in vivo, but they remain confined to the vicinity of amyloid plaques and do not impair cognition at levels relevant to AD. Type 1 oligomers are unrelated to amyloid fibrils and may have greater potential to cause global neural dysfunction in AD because they are dispersed. These results refine our understanding of the pathogenicity of Aβ oligomers in vivo.

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