Rights statement: 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
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Available under license: CC BY-NC-ND: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License
Final published version
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
}
TY - JOUR
T1 - Retro-inverso peptide inhibitor nanoparticles as potent inhibitors of aggregation of the Alzheimer’s Aβ peptide
AU - Gregori, Maria
AU - Taylor, Mark Neville
AU - Salvati, Elisa
AU - Re, Francesca
AU - Mancini, Simona
AU - Balducci, Claudia
AU - Forloni, Gianluigi
AU - Zambelli, Vanessa
AU - Sesana, Silvia
AU - Michael, Maria
AU - Michail, Christos
AU - Kolosov, Oleg Victor
AU - Tinker-Mill, Claire Louisa
AU - Sherer, Mike
AU - Harris, Stephen
AU - Fullwood, Nigel James
AU - Masserini, Massimo
AU - Allsop, David
N1 - 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
PY - 2017/2
Y1 - 2017/2
N2 - 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.
AB - 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.
KW - Alzheimer’s disease
KW - liposomes
KW - retro-inverso peptide
KW - β-amyloid
KW - oligomer
U2 - 10.1016/j.nano.2016.10.006
DO - 10.1016/j.nano.2016.10.006
M3 - Journal article
VL - 13
SP - 723
EP - 732
JO - Nanomedicine: Nanotechnology, Biology, and Medicine
JF - Nanomedicine: Nanotechnology, Biology, and Medicine
SN - 1549-9642
IS - 2
ER -