Astrocytes contain amyloid-β annular protofibrils in Alzheimer’s disease brains

Annular protofibrils (APFs) represent a newly described and distinct class of amyloid structures formed by disease-associated proteins. In vitro, these pore-like structures have been implicated in membrane permeabilization and ion homeostasis via pore formation. Still, their formation and relevance in vivo are poorly understood. Herein, we report that APFs are in human Alzheimer’s disease brain samples and that amyloid-β APFs were associated with activated astrocytes. Moreover, we show that amyloid-β APFs in astrocytes adopt a conformation in which the N-terminal region is buried inside the wall of the pore. Our results together with previous studies suggest that the formation of amyloid-β APFs in astrocytes could be a relevant event in the pathogenesis of Alzheimer’s disease and validate this amyloidogenic structure as a target for the prevention of the disease.

► Amyloid oligomers/protofibrils may cause cell death in Alzheimer’s disease (AD). ► Reactive astrocytes are present in AD brains. ► Amyloid-β has been detected in astrocytes surrounding amyloid plaques. ► Amyloid-β annular protofibrils are present in astrocytes of AD brains. ► Amyloid annular protofibrils formation in astrocytes contribute to AD pathogenesis.