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Peptide aptamer targeting Aβ–PrP–Fyn axis reduces Alzheimer’s disease pathologies in 5XFAD transgenic mouse model

Currently, no effective therapeutics exist for the treatment of incurable neurodegenerative diseases such as Alzheimer’s disease (AD). The cellular prion protein (PrP(C)) acts as a high-affinity receptor for amyloid beta oligomers (AβO), a main neurotoxic species mediating AD pathology. The interact...

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Autores principales: Ali, Tahir, Klein, Antonia N., Vu, Alex, Arifin, Maria I., Hannaoui, Samia, Gilch, Sabine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10164677/
https://www.ncbi.nlm.nih.gov/pubmed/37149826
http://dx.doi.org/10.1007/s00018-023-04785-w
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author Ali, Tahir
Klein, Antonia N.
Vu, Alex
Arifin, Maria I.
Hannaoui, Samia
Gilch, Sabine
author_facet Ali, Tahir
Klein, Antonia N.
Vu, Alex
Arifin, Maria I.
Hannaoui, Samia
Gilch, Sabine
author_sort Ali, Tahir
collection PubMed
description Currently, no effective therapeutics exist for the treatment of incurable neurodegenerative diseases such as Alzheimer’s disease (AD). The cellular prion protein (PrP(C)) acts as a high-affinity receptor for amyloid beta oligomers (AβO), a main neurotoxic species mediating AD pathology. The interaction of AβO with PrP(C) subsequently activates Fyn tyrosine kinase and neuroinflammation. Herein, we used our previously developed peptide aptamer 8 (PA8) binding to PrP(C) as a therapeutic to target the AβO–PrP–Fyn axis and prevent its associated pathologies. Our in vitro results indicated that PA8 prevents the binding of AβO with PrP(C) and reduces AβO-induced neurotoxicity in mouse neuroblastoma N2a cells and primary hippocampal neurons. Next, we performed in vivo experiments using the transgenic 5XFAD mouse model of AD. The 5XFAD mice were treated with PA8 and its scaffold protein thioredoxin A (Trx) at a 14.4 µg/day dosage for 12 weeks by intraventricular infusion through Alzet(®) osmotic pumps. We observed that treatment with PA8 improves learning and memory functions of 5XFAD mice as compared to Trx-treated 5XFAD mice. We found that PA8 treatment significantly reduces AβO levels and Aβ plaques in the brain tissue of 5XFAD mice. Interestingly, PA8 significantly reduces AβO–PrP interaction and its downstream signaling such as phosphorylation of Fyn kinase, reactive gliosis as well as apoptotic neurodegeneration in the 5XFAD mice compared to Trx-treated 5XFAD mice. Collectively, our results demonstrate that treatment with PA8 targeting the AβO–PrP–Fyn axis is a promising and novel approach to prevent and treat AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-023-04785-w.
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spelling pubmed-101646772023-05-09 Peptide aptamer targeting Aβ–PrP–Fyn axis reduces Alzheimer’s disease pathologies in 5XFAD transgenic mouse model Ali, Tahir Klein, Antonia N. Vu, Alex Arifin, Maria I. Hannaoui, Samia Gilch, Sabine Cell Mol Life Sci Original Article Currently, no effective therapeutics exist for the treatment of incurable neurodegenerative diseases such as Alzheimer’s disease (AD). The cellular prion protein (PrP(C)) acts as a high-affinity receptor for amyloid beta oligomers (AβO), a main neurotoxic species mediating AD pathology. The interaction of AβO with PrP(C) subsequently activates Fyn tyrosine kinase and neuroinflammation. Herein, we used our previously developed peptide aptamer 8 (PA8) binding to PrP(C) as a therapeutic to target the AβO–PrP–Fyn axis and prevent its associated pathologies. Our in vitro results indicated that PA8 prevents the binding of AβO with PrP(C) and reduces AβO-induced neurotoxicity in mouse neuroblastoma N2a cells and primary hippocampal neurons. Next, we performed in vivo experiments using the transgenic 5XFAD mouse model of AD. The 5XFAD mice were treated with PA8 and its scaffold protein thioredoxin A (Trx) at a 14.4 µg/day dosage for 12 weeks by intraventricular infusion through Alzet(®) osmotic pumps. We observed that treatment with PA8 improves learning and memory functions of 5XFAD mice as compared to Trx-treated 5XFAD mice. We found that PA8 treatment significantly reduces AβO levels and Aβ plaques in the brain tissue of 5XFAD mice. Interestingly, PA8 significantly reduces AβO–PrP interaction and its downstream signaling such as phosphorylation of Fyn kinase, reactive gliosis as well as apoptotic neurodegeneration in the 5XFAD mice compared to Trx-treated 5XFAD mice. Collectively, our results demonstrate that treatment with PA8 targeting the AβO–PrP–Fyn axis is a promising and novel approach to prevent and treat AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-023-04785-w. Springer International Publishing 2023-05-07 2023 /pmc/articles/PMC10164677/ /pubmed/37149826 http://dx.doi.org/10.1007/s00018-023-04785-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Ali, Tahir
Klein, Antonia N.
Vu, Alex
Arifin, Maria I.
Hannaoui, Samia
Gilch, Sabine
Peptide aptamer targeting Aβ–PrP–Fyn axis reduces Alzheimer’s disease pathologies in 5XFAD transgenic mouse model
title Peptide aptamer targeting Aβ–PrP–Fyn axis reduces Alzheimer’s disease pathologies in 5XFAD transgenic mouse model
title_full Peptide aptamer targeting Aβ–PrP–Fyn axis reduces Alzheimer’s disease pathologies in 5XFAD transgenic mouse model
title_fullStr Peptide aptamer targeting Aβ–PrP–Fyn axis reduces Alzheimer’s disease pathologies in 5XFAD transgenic mouse model
title_full_unstemmed Peptide aptamer targeting Aβ–PrP–Fyn axis reduces Alzheimer’s disease pathologies in 5XFAD transgenic mouse model
title_short Peptide aptamer targeting Aβ–PrP–Fyn axis reduces Alzheimer’s disease pathologies in 5XFAD transgenic mouse model
title_sort peptide aptamer targeting aβ–prp–fyn axis reduces alzheimer’s disease pathologies in 5xfad transgenic mouse model
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10164677/
https://www.ncbi.nlm.nih.gov/pubmed/37149826
http://dx.doi.org/10.1007/s00018-023-04785-w
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