Cyclization of Peptides Enhances the Inhibitory Activity against Ganglioside-Induced Aβ Fibril Formation

• Published in: ACS chemical neuroscience 2023-12, Vol.14 (23), p.4199-4207
• Main Authors: Miyamoto, Erika, Sato, Toshinori, Matsubara, Teruhiko
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Amyloid beta-Peptides - metabolism; Cyclization; G(M1) Ganglioside - chemistry; Gangliosides - metabolism; Humans; Neurodegenerative Diseases; Peptides, Cyclic - metabolism; Peptides, Cyclic - pharmacology
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.3c00589

Alzheimer's disease is a progressive neurodegenerative disease and is the most common cause of dementia. It has been reported that the assembly of amyloid β-protein (Aβ) on the cell membrane is induced by the interaction of the Aβ monomer with gangliosides such as GM1. The ganglioside-bound Aβ (GAβ) complex acts as a seed to promote the toxic assembly of the Aβ fibrils. In a previous study, we found that a GM1 cluster-binding peptide (GCBP) specifically recognizes Aβ-sensitive ganglioside nanoclusters and inhibits the assembly of Aβ on a GM1-containing lipid membrane. In this study, cysteine-substituted double mutants of GCBP were designed and cyclized by intramolecular disulfide bond formation. Affinity assays indicated that one of the cyclic peptides had a higher affinity to a GM1-containing membrane compared to that of GCBP. Furthermore, surface topography analysis indicated that this peptide recognizes GM1 nanoclusters on the lipid membrane. An evaluation of the inhibitory kinetics indicated that the cyclic peptide could inhibit the formation of Aβ fibrils with an IC value of 1.2 fM, which is 10,000-fold higher than that of GCBP. The cyclic peptide was also shown to have a clearance effect on Aβ fibrils deposited on the lipid membrane and suppressed the formation of toxic Aβ assemblies. Our results indicate that the cyclic peptide that binds to the Aβ-sensitive ganglioside nanocluster is a potential novel inhibitor of ganglioside-induced Aβ assembly.