Protein Structure and Folding
Small Liposomes Accelerate the Fibrillation of Amyloid β (1–40)*

https://doi.org/10.1074/jbc.M114.592527Get rights and content
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The deposition of amyloid β (Aβ) peptides is a pathological hallmark of Alzheimer disease. Aβ peptides were previously considered to interact specifically with ganglioside-containing membranes. Several studies have suggested that Aβ peptides also bind to phosphatidylcholine membranes, which lead to deformation of membranes and fibrillation of Aβ. Moreover, the role of membrane curvature, one type of deformation produced by binding of proteins to a membrane, in the binding and fibrillation of Aβ remains unclear. To clearly understand the relationship between the binding, consequent membrane deformation, and fibrillation of Aβ, we examined the amyloid fibrillation of Aβ-(1–40) in the presence of liposomes of various sizes. Membrane curvature increased with a decrease in the size of the liposomes. We used liposomes made of 1,2-dioleoyl-sn-glycero-3-phosphocholine to eliminate electrostatic effects. The results obtained showed that liposomes of smaller sizes (≤50 nm) significantly accelerated the nucleation step, thereby shortening the lag time of fibrillation. On the other hand, liposomes of larger sizes decreased the amount of fibrils but did not notably affect the lag time. The morphologies of fibrils, which were monitored by total internal reflection fluorescence microscopy, atomic force microscopy, and transmission electron microscopy, revealed that the length of Aβ-(1–40) fibrils became shorter and the amount of amorphous aggregates became larger as liposomes increased in size. These results suggest that the curvature of membranes coupled with an increase in water-accessible hydrophobic regions is important for binding and concentrating Aβ monomers, leading to amyloid nucleation. Furthermore, amyloid fibrillation on membranes may compete with non-productive binding to produce amorphous aggregates.Aggregation and fibrillation of amyloid β peptides (Aβ) in lipid bilayers lead to membrane disruption.

Results

Small vesicles accelerated Aβ fibrillation, whereas large vesicles promoted amorphous aggregation.

Conclusion

Moderate membrane-curvature-dependent interaction is an important factor for Aβ aggregation.

Significance

Two types of membrane binding, one leading to amyloid nucleation and the other to non-productive binding, may be common to various amyloidogenic proteins.

Amyloid
Amyloid-β (AB)
Lipid
Membrane
Protein Aggregation
Amyloid Fibrils
Supersaturation

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*

This work was supported by the Ministry of Education, Science, Sports, and Culture, Japan, a grant-in-aid for scientific research (to Y. G.), and a grant-in-aid for the Japan Society for the Promotion of Science Fellows (to M. S. T.). We acknowledge financial support from Takeda Science Foundation (to H. Y.).

1

Present address: Dept. of Chemistry and Biotechnology, Graduate School of Engineering, and Center for Research on Green Sustainable Chemistry, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan.