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
Authors | Parthsarathy, V., McClean, P.L., Hölscher, C., Taylor, M., Tinker, C., Jones, G., Kolosov, O., Salvati, E., Gregori, M., Masserini, M. and Allsop, D. |
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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. |
Keywords | Alzheimer's disease; peptide; neurogenesis |
Year | 2013 |
Journal | PLos ONE |
Journal citation | 8 (1) |
Publisher | Public Library of Science (PLoS) |
ISSN | 1932-6203 |
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 status | Published |
Publication dates | 31 Jan 2013 |
Publication process dates | |
Deposited | 26 May 2022 |
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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