Cryo‐electron Microscopy Imaging of Alzheimer's Amyloid‐beta 42 Oligomer Displayed on a Functionally and Structurally Relevant Scaffold

Amyloid‐β peptide (Aβ) oligomers are pathogenic species of amyloid aggregates in Alzheimer's disease. Like certain protein toxins, Aβ oligomers permeabilize cellular membranes, presumably through a pore formation mechanism. Owing to their structural and stoichiometric heterogeneity, the structure of these pores remains to be characterized. We studied a functional Aβ42‐pore equivalent, created by fusing Aβ42 to the oligomerizing, soluble domain of the α‐hemolysin (αHL) toxin. Our data reveal Aβ42‐αHL oligomers to share major structural, functional, and biological properties with wild‐type Aβ42‐pores. Single‐particle cryo‐EM analysis of Aβ42‐αHL oligomers (with an overall 3.3 Å resolution) reveals the Aβ42‐pore region to be intrinsically flexible. The Aβ42‐αHL oligomers will allow many of the features of the wild‐type amyloid oligomers to be studied that cannot be otherwise, and may be a highly specific antigen for the development of immuno‐base diagnostics and therapies. A functional and structural Aβ42‐oligomer equivalent, created by fusing Aβ42 to the oligomerizing, soluble domain of the α‐hemolysin (αHL) toxin, shares major structural, functional, and biological properties with Alzheimer's wild‐type Aβ42 oligomers. Cryo‐EM studies reveal that the αHL‐displayed oligomers structurally remain in a well‐defined stoichiometry, providing a stable mimetic antigen for the development of conformation‐specific antibodies.