Amyloid-β, the peptide that forms the hallmark plaques of Alzheimer disease, can exist in a variety of forms, including monomers, soluble oligomers, and fully fledged fibrils. The oligomers, or protofibrils, are generally thought to be intermediates on the way to true fibrils (but see ARF related news story), and have been shown to be the most toxic to cells (see ARF related news story and ARF news story). But what is the basis for this toxicity? In an accelerated publication in the Journal of Biological Chemistry, Charlie Glabe and colleagues from the University of California, Irvine, show that protofibrils formed from several different amyloidogenic peptides are all toxic in the same way—they permeabilize lipid bilayers, increasing the flux of ions across the membrane.
Glabe and colleagues were drawn to the plasma membrane as a likely site of toxicity because amyloid aggregates are known to be toxic no matter which side of the membrane they are on. First author Rakez Kayed and colleagues tested various forms of Aβ1-42 species for their ability to alter conductance of a planar lipid bilayer. They found that monomers, dimers, and fibrils had no effect, but oligomers, specifically those forming spherical particles of 3-5 nanometers in diameter, dramatically increased current through the membrane. The effect was rapidly reversed when the authors added an anti-Aβ oligomer antibody. This suggests two things, the authors write. One, when they interact with the membrane, oligomers of Aβ do not change to a conformation unrecognized by the antibody. And two, the oligomers are likely associating with the periphery of the membrane, not becoming embedded in it.
How these oligomers affect conductance is unclear. However, they do not appear to be targeted to specific ion channels because Kayed and colleagues found that the conductance elicited is not ion selective. Previous reports have indicated that Aβ can form ion channels in the membrane and that these are inhibited by Congo red (see for example Kagan et al., 2002), but the authors found that this dye had no effect on the conductance. “Rather than forming pores or channels, soluble oligomers appear to enhance the ability of ions to move through the lipid bilayer on their own,” write the authors. The difference between these and previous experiments that found Aβ channel conductance could be the absence of significant numbers of soluble amyloid oligomers in the earlier work, the authors suggest.
The effect on lipid bilayer conductance is not limited to oligomers of Aβ. When Kayed and colleagues carried out the same experiments with oligomers of α-synuclein, IAPP, a poly Q peptide, and a prion peptide, they found that soluble oligomers of these peptides, but again not low-molecular-weight species or fibrils, caused dramatic increases in membrane conductance. Hence, “this effect is specific for the particular conformation associated with spherical oligomers,” note the authors. The results also suggest a common mechanism of pathogenesis for a variety of amyloidogenic peptides.—Tom Fagan
- Amyloid Formation—Taking Things One Monomer at a Time
- "Arctic" APP Mutation Supports Protofibril Role
- Post-Conference News: Oligomers, Protofibrils, and Fibrils—They Are All Bad
- Kagan BL, Hirakura Y, Azimov R, Azimova R, Lin MC. The channel hypothesis of Alzheimer's disease: current status. Peptides. 2002 Jul;23(7):1311-5. PubMed.
- Kayed R, Sokolov Y, Edmonds B, McIntire TM, Milton SC, Hall JE, Glabe CG. Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J Biol Chem. 2004 Nov 5;279(45):46363-6. PubMed.