A tailored tetravalent peptide displays dual functions to inhibit amyloid ß production and aggregation.

Inhibition of amyloid-ß peptide (Aß) accumulation in the brain is a promising approach for treatment of Alzheimer's disease (AD). Aß is produced by ß-secretase and γ-secretase in endosomes via sequential proteolysis of amyloid precursor protein (APP). Aß 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 Aß via multivalent interactions. In cells, LME-tet-bound APP in the plasma membrane is transported to endosomes, blocking Aß production through specific inhibition of ß-cleavage, but not γ-cleavage. LME-tet further suppresses Aß aggregation by blocking formation of the ß-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 Aß levels in the brain of AD model mice, suggesting it may hold promise for treatment of AD.