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

R. J. Elsworthy; J. A. Crowe; M. C. King; C. Dunleavy; E. Fisher; A. Ludlam; H. R. Parri; E. J. Hill; S. Aldred

doi:10.1038/s41398-022-02050-5

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

R. J. Elsworthy^*, J. A. Crowe, M. C. King, C. Dunleavy, E. Fisher, A. Ludlam, H. R. Parri, E. J. Hill^*, S. Aldred

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	285
Journal	Translational psychiatry
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41398-022-02050-5
Publication status	Published - 18 Jul 2022

Bibliographical note

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 http://creativecommons.org/licenses/by/4.0/.

Funding: This work was supported by Alzheimer’s Research UK [ARUK-MID2019].

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

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10.1038/s41398-022-02050-5Licence: CC BY 4.0

The effect of citalopram treatment
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 http://creativecommons.org/licenses/by/4.0/.
Final published version, 1.81 MBLicence: CC BY 4.0

Cite this

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

abstract = "Selective Serotonin Reuptake Inhibitors (SSRIs) may hold therapeutic benefits for people with Alzheimer{\textquoteright}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.",

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",

author = "Elsworthy, {R. J.} and Crowe, {J. A.} and King, {M. C.} and C. Dunleavy and E. Fisher and A. Ludlam and Parri, {H. R.} and Hill, {E. J.} and S. Aldred",

note = "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{\textquoteright}s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}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 http://creativecommons.org/licenses/by/4.0/. Funding: This work was supported by Alzheimer{\textquoteright}s Research UK [ARUK-MID2019].",

year = "2022",

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doi = "10.1038/s41398-022-02050-5",

language = "English",

volume = "12",

journal = "Translational psychiatry",

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AU - Elsworthy, R. J.

AU - Crowe, J. A.

AU - King, M. C.

AU - Dunleavy, C.

AU - Fisher, E.

AU - Ludlam, A.

AU - Parri, H. R.

AU - Hill, E. J.

AU - Aldred, S.

N1 - 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 http://creativecommons.org/licenses/by/4.0/. Funding: This work was supported by Alzheimer’s Research UK [ARUK-MID2019].

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N2 - 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.

AB - 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.

KW - Alzheimer Disease/genetics

KW - Amyloid Precursor Protein Secretases/genetics

KW - Amyloid beta-Peptides/metabolism

KW - Amyloid beta-Protein Precursor/genetics

KW - Citalopram/pharmacology

KW - Flavin-Adenine Dinucleotide/metabolism

KW - Humans

KW - Neurons/metabolism

KW - Oxidative Stress

KW - Presenilin-1/genetics

KW - Serotonin Uptake Inhibitors/pharmacology

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DO - 10.1038/s41398-022-02050-5

M3 - Article

C2 - 35851379

SN - 2158-3188

VL - 12

JO - Translational psychiatry

JF - Translational psychiatry

IS - 1

M1 - 285

ER -

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

Abstract

Bibliographical note

Keywords

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