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

Maria Gregori, Mark Taylor, Elisa Salvati, Francesca Re, Simona Mancini, Claudia Balducci, Gianluigi Forloni, Vanessa Zambelli, Silvia Sesana, Maria Michael, Christos Michail, Claire Tinker-Mill, Oleg Kolosov, Michael Sherer, Stephen Harris, Nigel J Fullwood, Massimo Masserini, David Allsop

Research output: Contribution to journalArticlepeer-review

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 BL/6 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.

Original languageEnglish
Pages (from-to)723-732
Number of pages10
JournalNanomedicine: Nanotechnology, Biology, and Medicine
Volume13
Issue number2
DOIs
Publication statusPublished - Feb 2017

Keywords

  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Animals
  • Blood-Brain Barrier
  • Humans
  • Liposomes
  • Mice, Transgenic
  • Nanoparticles
  • Peptide Fragments
  • Tumor Cells, Cultured
  • Journal Article

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