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

• Published in: Nanomedicine Vol. 13; no. 2; pp. 723 - 732
• Main Authors: Gregori, Maria, Taylor, Mark, Salvati, Elisa, Re, Francesca, Mancini, Simona, Balducci, Claudia, Forloni, Gianluigi, Zambelli, Vanessa, Sesana, Silvia, Michael, Maria, Michail, Christos, Tinker-Mill, Claire, Kolosov, Oleg, Scherer, Michael, Harris, Stephen, Fullwood, Nigel J, Masserini, Massimo, Allsop, David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2017
• Subjects: Alzheimer Disease - physiopathology; Alzheimer Disease - therapy; Alzheimer's disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Humans; Internal Medicine; Liposomes; Mice, Transgenic; Nanoparticles; Oligomer; Peptide Fragments; Retro-inverso peptide; Tumor Cells, Cultured; β-amyloid; oligomer; retro-inverso peptide; liposomes; Alzheimer's disease; β-amyloid; Liposomes; Retro-inverso peptide; Oligomer
• ISSN: 1549-9634; 1549-9642; 1549-9642
• DOI: 10.1016/j.nano.2016.10.006

Abstract Aggregation of Amyloid-β peptide (Aβ) 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 Aβ. Remarkably low concentrations of these peptide inhibitor nanoparticles (PINPs) were required to inhibit the formation of Aβ oligomers and fibrils in vitro , with 50% inhibition occurring at a molar ratio of ~1:2000 of liposome-bound RI-OR2-TAT to Aβ. PINPs also bound to Aβ with high affinity (Kd = 13.2–50 nM), rescued SHSY-5Y cells from the toxic effect of pre-aggregated Aβ, crossed an in vitro blood–brain-barrier model (hCMEC/D3 cell monolayer), entered the brains of C57/BL6 mice, and protected against memory loss in APPSWE transgenic mice in a novel object recognition test. As the most potent aggregation inhibitor that we have tested so far, we propose to develop PINPs as a potential disease-modifying treatment for AD.