Title
A Tailored Tetravalent Peptide Displays Dual Functions to Inhibit Amyloid β Production and Aggregation
Author
Sato, Waka, Miho Watanabe-Takahashi, Takuya Murata, Naoko Utsunomiya-Tate, Jun Motoyama, Masataka Anzai, Seiko Ishihara, Nanako Nishioka, Hina Uchiyama, Juri Togashi, Saeka Nishihara, Kiyoshi Kawasaki, Takashi Saito, Takaomi C. Saido, Satoru Funamoto, and Kiyotaka Nishikawa
Year
2023
Journal
Communications Biology
Abstract
Inhibition of amyloid-β peptide (Aβ) accumulation in the brain is a promising approach for treatment of Alzheimer’s disease (AD). Aβ is produced by β-secretase and γ-secretase in endosomes via sequential proteolysis of amyloid precursor protein (APP). Aβ and APP have a common feature to readily cluster to form multimers. Here, using multivalent peptide library screens, we identified a tetravalent peptide, LME-tet, which binds APP and Aβ via multivalent interactions. In cells, LME-tet-bound APP in the plasma membrane is transported to endosomes, blocking Aβ production through specific inhibition of β-cleavage, but not γ-cleavage. LME-tet further suppresses Aβ aggregation by blocking formation of the β-sheet conformation. Inhibitory effects are not observed with a monomeric peptide, emphasizing the significance of multivalent interactions for mediating these activities. Critically, LME-tet efficiently reduces Aβ levels in the brain of AD model mice, suggesting it may hold promise for treatment of AD.
Full Article
Instrument
J-1500,FP-8300
Keywords
Alzheimer’s disease (AD),Multivalent peptide library screens