Quaternary Structure Defi nes a Large Class of Amyloid-b Oligomers Neutralized by Sequestration Graphical

Graphical Abstract Highlights d Brain-derived amyloid-b oligomers (Abo) are classified as type 1 and type 2 d Type 1 Abo, A11-immunoreactive, have no spatiotemporal relationship with Ab plaques d Type 2 Abo, OC-immunoreactive, emerge after and accumulate around Ab plaques d Type 2 Abo, despite being highly abundant, do not impair cognition in situ In Brief Liu et al. classify brain-derived amyloid-b oligomers into type 1 and type 2. Type 2, but not type 1, oligomers have a spatiotemporal and structural relationship with amyloid plaques. Highly abundant type 2 oligomers do not impair cognition in situ, possibly due to spatial sequestration around plaques. SUMMARY The accumulation of amyloid-b (Ab) 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 Ab oligo-mers 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 fi-brils and may have greater potential to cause global neural dysfunction in AD because they are dispersed. These results refine our understanding of the patho-genicity of Ab oligomers in vivo.

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