Retro-inverso peptide inhibitor nanoparticles as potent inhibitors of aggregation of the Alzheimer's Aβ peptide

Aggregation of amyloid-beta peptide (A beta) is a key event in the pathogenesis of Alzheimer's disease (AD). We investigated the effects of nanoliposomes decorated with the retro-inverso peptide RI-OR2-TAT (Ac-rGffvlkGrrrrqrrkkrGy-NH2) on the aggregation and toxicity of Aa. Remarkably low concentrations of these peptide inhibitor nanoparticles (PINPs) were required to inhibit the formation of A beta oligomers and fibrils in vitro, with 50% inhibition occurring at a molar ratio of similar to 1: 2000 of liposome-bound RI-OR2-TAT to Aa. PINPs also bound to Aa with high affinity (Kd = 13.2-50 nM), rescued SHSY-5Y cells from the toxic effect of pre-aggregated Aa, crossed an in vitro blood-brain barrier model (hCMECD3 cellmonolayer), entered the brains of C57BL6mice, and protected againstmemory loss inAPPSWE transgenic mice in a novel object recognition test. As themost potent aggregation inhibitor that we have tested so far, we propose to develop PINPs as a potential disease-modifying treatment for AD. (C)2016 Elsevier Inc. All rights reserved.