3D-visualization of amyloid-β oligomer interactions with lipid membranes by cryo-electron tomography

Abstract

Amyloid-β (Aβ) assemblies have been shown to bind to lipid bilayers. This can disrupt membrane integrity and cause a loss of cellular homeostasis, that triggers a cascade of events leading...

Anatomy and formation mechanisms of early amyloid-β oligomers with lateral branching: graph network analysis on large-scale simulations

“…We found that these AβOs displayed curvilinear, irregular shapes with occasional lateral branches, consistent with AβO morphologies reported by recent cryo-ET experiments. 28 Aβ40 oligomers were more likely to develop branches than Aβ42 oligomers, which may explain the tendency of Aβ40, but not Aβ42, to be trapped in network-like aggregates, as reported previously, 20,25…”

“…44,45,47,48,63 This predicted that the of Aβ42 oligomers is indeed larger than that of 𝐶 ∞ Aβ40 (3.00 versus 2.28), since on average Aβ42 oligomers have a have recently been reported in several studies using advanced imaging techniques such as high-resolution AFM, solution TEM, and cryo-ET. 20,25,28 We evaluated the degree of branching in AβOs by counting the number of branches ( ) present in these oligomers. This 𝑏 quantity was calculated by finding disconnected components after the entire backbone part was removed from the topological networks.…”

“…13,[25][26][27] Recently, threedimensional imaging of elongated AβOs with high-resolution cryo-electron tomography (cryoET) revealed that the curvilinear aggregates were more irregular than previously thought and exhibited branched structures. 28 Despite these structural insights, it remains largely unclear how Aβ peptides are spatially organized within AβOs, how they are packed against each other, and how these structural properties are realized through self-assembly. Addressing these questions is key to elucidating AβO assembly mechanisms.…”

In vitro reconstitution demonstrates the amyloid-beta mediated myelin membrane deformation

“…The striking reduction in the surface pressure can be attributed to the generation of load by the growing fibrils (Xue et al, 2009) or the extraction of lipids by the monomeric/oligomeric Aβ-40 and the lack of interleaflet coupling in the membrane monolayer (Harayama & Riezman, 2018). The above early time scale observations combined with the late time scale microscopic observations are in line with a recent report suggesting insertion of oligomer and protofibrils on liposomes observed by 3D Cryo-electron tomography (Tian et al, 2021). We think that although the monomeric or low oligomeric Aβ-40 may insert into the membrane depending on the depth of the lipid packing defect, however, the fibrillation takes place at the membrane interface, as evident from the lack of increase in surface pressure corresponding to surface insertion (Fig.…”

Distinct modes of action of IAPP oligomers on membranes

“…N21P was found to accelerate selfassembly and to be as toxic as wild type, but N21G was not toxic 101 . Other possible approaches include cryoET, which has been recently applied to Ab oligomers 102 . Interestingly, when de novo designed β barrels were too stable they were found to form amyloid 76 , showing a link between these two states.…”