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

doi:10.1016/j.nano.2016.10.006

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 journal › Article › peer-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 language	English
Pages (from-to)	723-732
Number of pages	10
Journal	Nanomedicine: Nanotechnology, Biology, and Medicine
Volume	13
Issue number	2
DOIs	https://doi.org/10.1016/j.nano.2016.10.006
Publication status	Published - 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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10.1016/j.nano.2016.10.006

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Gregori, M., Taylor, M., Salvati, E., Re, F., Mancini, S., Balducci, C., Forloni, G., Zambelli, V., Sesana, S., Michael, M., Michail, C., Tinker-Mill, C., Kolosov, O., Sherer, M., Harris, S., Fullwood, N. J., Masserini, M., & Allsop, D. (2017). Retro-inverso peptide inhibitor nanoparticles as potent inhibitors of aggregation of the Alzheimer's Aβ peptide. Nanomedicine: Nanotechnology, Biology, and Medicine, 13(2), 723-732. https://doi.org/10.1016/j.nano.2016.10.006

Gregori, M, Taylor, M, Salvati, E, Re, F, Mancini, S, Balducci, C , Forloni, G, Zambelli, V, Sesana, S, Michael, M, Michail, C, Tinker-Mill, C, Kolosov, O, Sherer, M, Harris, S, Fullwood, NJ, Masserini, M & Allsop, D 2017, 'Retro-inverso peptide inhibitor nanoparticles as potent inhibitors of aggregation of the Alzheimer's Aβ peptide', Nanomedicine: Nanotechnology, Biology, and Medicine, vol. 13, no. 2, pp. 723-732. https://doi.org/10.1016/j.nano.2016.10.006

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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 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.",

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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AU - Gregori, Maria

AU - Taylor, Mark

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 - Tinker-Mill, Claire

AU - Kolosov, Oleg

AU - Sherer, Michael

AU - Harris, Stephen

AU - Fullwood, Nigel J

AU - Masserini, Massimo

AU - Allsop, David

PY - 2017/2

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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 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.

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 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.

KW - Alzheimer Disease

KW - Amyloid beta-Peptides

KW - Animals

KW - Blood-Brain Barrier

KW - Humans

KW - Liposomes

KW - Mice, Transgenic

KW - Nanoparticles

KW - Peptide Fragments

KW - Tumor Cells, Cultured

KW - Journal Article

U2 - 10.1016/j.nano.2016.10.006

DO - 10.1016/j.nano.2016.10.006

M3 - Article

C2 - 27769888

VL - 13

SP - 723

EP - 732

JO - Nanomedicine: Nanotechnology, Biology, and Medicine

JF - Nanomedicine: Nanotechnology, Biology, and Medicine

SN - 1549-9634

IS - 2

ER -

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

Abstract

Keywords

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