Ganglioside Nanocluster-Targeting Peptidyl Inhibitor Prevents Amyloid β Fibril Formation on the Neuronal Membrane

Teruhiko Matsubara, Mako Nakai, Masaya Nishihara, Erika Miyamoto, Toshinori Sato

Research output: Contribution to journalArticlepeer-review

Abstract

Neurotoxicity caused by peptide and protein aggregates is associated with the onset of neurodegenerative diseases. Accumulation of the amyloid β protein (Aβ) induced by neuronal ganglioside-enriched nanodomains (nanoclusters) in the presynaptic neuronal membrane, resulting in toxic oligomeric and fibrous forms, is implicated in the onset of Alzheimer's disease (AD). In the current study, we found that the ganglioside cluster-binding peptide (GCBP), a pentadecapeptide VWRLLAPPFSNRLLP that binds to ganglioside-enriched nanoclusters, inhibits the formation of Aβ assemblies with an IC50 of 12 pM and also removes Aβ fibrils deposited on the lipid membrane. Thus, in addition to inhibiting Aβ assembly formation, GCBP effectively clears toxic Aβ assemblies as well, thereby suppressing neuronal cellular damage and death induced by such assemblies. These results indicate that ganglioside cluster-binding molecules may act as novel Aβ-targeting drugs with a unique mechanism of action that may be utilized to ameliorate AD.

Original languageEnglish
Pages (from-to)1868-1876
Number of pages9
JournalACS Chemical Neuroscience
Volume13
Issue number13
DOIs
Publication statusPublished - 2022 Jul 6

Keywords

  • Alzheimer's disease
  • amyloid β protein
  • atomic force microscopy
  • clearance
  • ganglioside nanocluster
  • inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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