Exploring the molecular mechanisms of MSC-derived exosomes in Alzheimer's disease: Autophagy, insulin and the PI3K/Akt/mTOR signaling pathway.

Ebrahim, Nesrine; Al Saihati, Hajer A; Alali, Zahraa; Aleniz, Faris Q; Mahmoud, Sabry Younis Mohamed; Badr, Omnia A; Dessouky, Arigue A; Mostafa, Ola; Hussien, Noha I; Farid, Ayman Samir; El-Sherbiny, Mohamed; Salim, Rabab F; Forsyth, Nicholas Robert; Ali, Fares E M; Alsabeelah, Nimer F

Abstract

Alzheimer's disease (AD) is a devastating neurological condition characterized by cognitive decline, motor coordination impairment, and amyloid plaque accumulation. The underlying molecular mechanisms involve oxidative stress, inflammation, and neuronal degeneration. This study aimed to investigate the therapeutic effects of mesenchymal stem cell-derived exosomes (MSC-exos) on AD and explore the molecular pathways involved, including the PI3K/Akt/mTOR axis, autophagy, and neuroinflammation. To assess the potential of MSC-exos for the treatment of AD, rats were treated with AlCl (17 mg/kg/once/day) for 8 weeks, followed by the administration of an autophagy activator (rapamycin), or MSC-exos with or without an autophagy inhibitor (3-methyladenin; 3-MA+ chloroquine) for 4 weeks. Memory impairment was tested, and brain tissues were collected for gene expression analyses, western blotting, histological studies, immunohistochemistry, and transmission electron microscopy. Remarkably, the administration of MSC-exos improved memory performance in AD rats and reduced the accumulation of amyloid-beta (Aβ) plaques and tau phosphorylation. Furthermore, MSC-exos promoted neurogenesis, enhanced synaptic function, and mitigated astrogliosis in AD brain tissues. These beneficial effects were associated with the modulation of autophagy and the PI3K/Akt/mTOR signalling pathway, as well as the inhibition of neuroinflammation. Additionally, MSC-exos were found to regulate specific microRNAs, including miRNA-21, miRNA-155, miRNA-17-5p, and miRNA-126-3p, further supporting their therapeutic potential. Histopathological and bioinformatic analyses confirmed these findings. This study provides compelling evidence that MSC-exos hold promise as a potential therapeutic approach for AD. By modulating the PI3K/Akt/mTOR axis, autophagy, and neuroinflammation, MSC-exos have the potential to improve memory, reduce Aβ accumulation, enhance neurogenesis, and mitigate astrogliosis. These findings shed light on the therapeutic potential of MSC-exos and highlight their role in combating AD. [Abstract copyright: Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.]

Citation

Ebrahim, N., Al Saihati, H. A., Alali, Z., Aleniz, F. Q., Mahmoud, S. Y. M., Badr, O. A., …Alsabeelah, N. F. (2024). Exploring the molecular mechanisms of MSC-derived exosomes in Alzheimer's disease: Autophagy, insulin and the PI3K/Akt/mTOR signaling pathway. Biomedicine and Pharmacotherapy, 176, Article 116836. https://doi.org/10.1016/j.biopha.2024.116836

• Journal Article Type: Article
• Acceptance Date: May 26, 2024
• Online Publication Date: Jun 7, 2024
• Publication Date: Jun 7, 2024
• Deposit Date: Jul 5, 2024
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
• Print ISSN: 0753-3322
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 176
• Article Number: 116836
• DOI: https://doi.org/10.1016/j.biopha.2024.116836
• Keywords: Alzheimer's disease, MSC-exos, PI3K/Akt/mTOR, Autophagy, Neuroinflammation
• Public URL: https://keele-repository.worktribe.com/output/858889
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0753332224007200?via%3Dihub