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

Gregori, Maria and Taylor, Mark Neville and Salvati, Elisa and Re, Francesca and Mancini, Simona and Balducci, Claudia and Forloni, Gianluigi and Zambelli, Vanessa and Sesana, Silvia and Michael, Maria and Michail, Christos and Kolosov, Oleg Victor and Tinker-Mill, Claire Louisa and Sherer, Mike and Harris, Stephen and Fullwood, Nigel James and Masserini, Massimo and Allsop, David (2017) Retro-inverso peptide inhibitor nanoparticles as potent inhibitors of aggregation of the Alzheimer’s Aβ peptide. Nanomedicine: Nanotechnology, Biology, and Medicine, 13 (2). pp. 723-732. ISSN 1549-9642

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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.

Item Type:
Journal Article
Journal or Publication Title:
Nanomedicine: Nanotechnology, Biology, and Medicine
Additional Information:
This is the author’s version of a work that was accepted for publication in Nanomedicine. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Nanomedicine, 13, 2, 2017 DOI: 10.1016/j.nano.2016.10.006
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/2700/2701
Subjects:
ID Code:
82304
Deposited By:
Deposited On:
20 Oct 2016 12:14
Refereed?:
Yes
Published?:
Published
Last Modified:
05 Apr 2020 04:14