A novel retro-inverso peptide inhibitor reduces amyloid deposition, oxidation and inflammation and stimulates neurogenesis in the APPswe/PS1ΔE9 mouse model of Alzheimer's disease

Journal article


Parthsarathy, V., McClean, P.L., Hölscher, C., Taylor, M., Tinker, C., Jones, G., Kolosov, O., Salvati, E., Gregori, M., Masserini, M. and Allsop, D. 2013. A novel retro-inverso peptide inhibitor reduces amyloid deposition, oxidation and inflammation and stimulates neurogenesis in the APPswe/PS1ΔE9 mouse model of Alzheimer's disease. PLos ONE. 8 (1). https://doi.org/10.1371/journal.pone.0054769
AuthorsParthsarathy, V., McClean, P.L., Hölscher, C., Taylor, M., Tinker, C., Jones, G., Kolosov, O., Salvati, E., Gregori, M., Masserini, M. and Allsop, D.
Abstract

Previously, we have developed a retro-inverso peptide inhibitor (RI-OR2, rGffvlkGr) that blocks the in vitro formation and toxicity of the Aβ oligomers which are thought to be a cause of neurodegeneration and memory loss in Alzheimer's disease. We have now attached a retro-inverted version of the HIV protein transduction domain 'TAT' to RI-OR2 to target this new inhibitor (RI-OR2-TAT, Ac-rGffvlkGrrrrqrrkkrGy-NH(2)) into the brain. Following its peripheral injection, a fluorescein-labelled version of RI-OR2-TAT was found to cross the blood brain barrier and bind to the amyloid plaques and activated microglial cells present in the cerebral cortex of 17-months-old APPswe/PS1ΔE9 transgenic mice. Daily intraperitoneal injection of RI-OR2-TAT (at 100 nmol/kg) for 21 days into 10-months-old APPswe/PS1ΔE9 mice resulted in a 25% reduction (p<0.01) in the cerebral cortex of Aβ oligomer levels, a 32% reduction (p<0.0001) of β-amyloid plaque count, a 44% reduction (p<0.0001) in the numbers of activated microglial cells, and a 25% reduction (p<0.0001) in oxidative damage, while the number of young neurons in the dentate gyrus was increased by 210% (p<0.0001), all compared to control APPswe/PS1ΔE9 mice injected with vehicle (saline) alone. Our data suggest that oxidative damage, inflammation, and inhibition of neurogenesis are all a downstream consequence of Aβ aggregation, and identify a novel brain-penetrant retro-inverso peptide inhibitor of Aβ oligomer formation for further testing in humans as a potential disease-modifying treatment for Alzheimer's disease.

KeywordsAlzheimer's disease; peptide; neurogenesis
Year2013
JournalPLos ONE
Journal citation8 (1)
PublisherPublic Library of Science (PLoS)
ISSN1932-6203
Digital Object Identifier (DOI)https://doi.org/10.1371/journal.pone.0054769
Web address (URL)https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054769
http://europepmc.org/abstract/med/23382963
Output statusPublished
Publication dates31 Jan 2013
Publication process dates
Deposited26 May 2022
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https://repository.derby.ac.uk/item/96yw8/a-novel-retro-inverso-peptide-inhibitor-reduces-amyloid-deposition-oxidation-and-inflammation-and-stimulates-neurogenesis-in-the-appswe-ps1-e9-mouse-model-of-alzheimer-s-disease

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