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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatr. Jun 22, 2016; 6(2): 208-214
Published online Jun 22, 2016. doi: 10.5498/wjp.v6.i2.208
Linking multiple pathogenic pathways in Alzheimer’s disease
Rami Bou Khalil, Elie Khoury, Salam Koussa
Rami Bou Khalil, Elie Khoury, Department of Psychiatry, Hotel Dieu de France Hospital, Saint Joseph University, PO Box 166830, Beirut, Lebanon
Salam Koussa, Department of Neurology, Hotel Dieu de France Hospital, Saint Joseph University, PO Box 166830, Beirut, Lebanon
Author contributions: Bou Khalil R conceived the manuscript’s idea, initiated the research on the subject and prepared a first draft for the minir-review; Khoury E completed the research and contributed to the final version of the manuscript; Koussa S contributed to the elaboration of the research idea and process; all authors have read and approved the final version of this manuscript.
Conflict-of-interest statement: None declared for all authors.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Rami Bou Khalil, MD, Department of Psychiatry, Hotel Dieu de France Hospital, Saint Joseph University, A. Naccache Boulevard Street, Achrafieh, PO Box 166830, Beirut, Lebanon. ramiboukhalil@hotmail.com
Telephone: +961-70-946430
Received: March 1, 2016
Peer-review started: March 1, 2016
First decision: March 22, 2016
Revised: April 24, 2016
Accepted: May 10, 2016
Article in press: May 11, 2016
Published online: June 22, 2016
Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder presenting as progressive cognitive decline with dementia that does not, to this day, benefit from any disease-modifying drug. Multiple etiologic pathways have been explored and demonstrate promising solutions. For example, iron ion chelators, such as deferoxamine, are a potential therapeutic solution around which future studies are being directed. Another promising domain is related to thrombin inhibitors. In this minireview, a common pathophysiological pathway is suggested for the pathogenesis of AD to prove that all these mechanisms converge onto the same cascade of neuroinflammatory events. This common pathway is initiated by the presence of vascular risk factors that induce brain tissue hypoxia, which leads to endothelial cell activation. However, the ensuing hypoxia stimulates the production and release of reactive oxygen species and pro-inflammatory proteins. Furthermore, the endothelial activation may become excessive and dysfunctional in predisposed individuals, leading to thrombin activation and iron ion decompartmentalization. The oxidative stress that results from these modifications in the neurovascular unit will eventually lead to neuronal and glial cell death, ultimately leading to the development of AD. Hence, future research in this field should focus on conducting trials with combinations of potentially efficient treatments, such as the combination of intranasal deferoxamine and direct thrombin inhibitors.

Keywords: Alzheimer’s disease, Etiologies, Iron, Oxidative stress, Thrombin, Vascular risk factors

Core tip: Patients with Alzheimer’s disease (AD) have not benefited from any disease-modifying drug until now. Multiple etiologic pathways have been explored and suggest promising solutions in the future. The iron chelator deferoxamine is one potential therapeutic solution around which future studies are being directed. Another potential therapeutic solution is related to thrombin inhibitors. In this minireview, a common pathophysiological pathway is suggested for the pathogenesis of AD that is initiated by the presence of vascular risk factors inducing brain tissue hypoxia and endothelial cell activation. In predisposed individuals, this can lead to thrombin activation and iron decompartmentalization. The resulting oxidative stress will eventually lead to neuronal and glial cell death.