The effect of citalopram treatment on amyloid-β precursor protein processing and oxidative stress in human hNSC-derived neurons


Selective Serotonin Reuptake Inhibitors (SSRIs) may hold therapeutic benefits for people with Alzheimer’s disease (AD). SSRIs may perturb AD progression, or the conversion from MCI to AD, via increased neurogenesis, reduced oxidative stress and/or favourable Amyloid-β Precursor Protein (AβPP) processing. This study used iPSC derived cortical neuronal cells carrying 3 different PSEN1 mutations, to investigate the effect of treatment with the SSRI, Citalopram on AβPP processing and oxidative stress. Control and PSEN1 mutation (L286V, A246E, M146L) iPSC-derived neurons were treated with Citalopram for 45 days. ADAM10 activity, AβPP processing and Aβ generation was measured in addition to cellular redox status. Citalopram treatment reduced the Aβ1-42:40 ratio in control but not in fAD PSEN1 cells. ADAM10 activity was increased with Citalopram treatments in fAD PSEN1 cell lines, which was also seen for sAβPPα secretion. Lower superoxide generation in fAD PSEN1 cells following Citalopram treatment was identified, although there was no effect on end markers of oxidative stress. Treatment with Citalopram appears to have little effect on Aβ generation in fADPSEN1 cells, but our findings suggest that treatment can significantly increase non-amyloidogenic AβPP processing and reduce oxidative stress. These changes may explain why SSRIs appear most effective in the prodromal period of the disease progression, as opposed to reducing established AD pathology. Further investigation of specific pathways conferring the beneficial effects of SSRIs treatment are warranted.

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Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences
College of Health & Life Sciences > Chronic and Communicable Conditions
College of Health & Life Sciences > Clinical and Systems Neuroscience
Additional Information: This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit Funding: This work was supported by Alzheimer’s Research UK [ARUK-MID2019].
Uncontrolled Keywords: Alzheimer Disease/genetics,Amyloid Precursor Protein Secretases/genetics,Amyloid beta-Peptides/metabolism,Amyloid beta-Protein Precursor/genetics,Citalopram/pharmacology,Flavin-Adenine Dinucleotide/metabolism,Humans,Neurons/metabolism,Oxidative Stress,Presenilin-1/genetics,Serotonin Uptake Inhibitors/pharmacology
Publication ISSN: 2158-3188
Last Modified: 22 May 2024 07:21
Date Deposited: 19 Jul 2022 08:22
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Related URLs: https://www.nat ... 398-022-02050-5 (Publisher URL)
PURE Output Type: Article
Published Date: 2022-07-18
Accepted Date: 2022-07-01
Submitted Date: 2021-10-21
Authors: Elsworthy, R. J.
Crowe, J. A.
King, M. C.
Dunleavy, C.
Fisher, E.
Ludlam, A.
Parri, H. R. (ORCID Profile 0000-0002-1412-2688)
Hill, E. J. (ORCID Profile 0000-0002-9419-1500)
Aldred, S.



Version: Published Version

License: Creative Commons Attribution

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