Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Elsworthy, R. J. ; Crowe, J. A. LU orcid ; King, M. C. ; Dunleavy, C. ; Fisher, E. ; Ludlam, A. ; Parri, H. R. ; Hill, E. J. and Aldred, S. (2022) In Translational Psychiatry 12(1).
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Translational Psychiatry
volume
12
issue
1
article number
285
publisher
Nature Publishing Group
external identifiers
  • pmid:35851379
  • scopus:85134551324
ISSN
2158-3188
DOI
10.1038/s41398-022-02050-5
language
English
LU publication?
yes
id
6d9d8d68-2732-43d2-8f90-b85edca9c663
date added to LUP
2022-09-23 14:42:59
date last changed
2024-07-09 02:40:06
@article{6d9d8d68-2732-43d2-8f90-b85edca9c663,
  abstract     = {{<p>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.</p>}},
  author       = {{Elsworthy, R. J. and Crowe, J. A. and King, M. C. and Dunleavy, C. and Fisher, E. and Ludlam, A. and Parri, H. R. and Hill, E. J. and Aldred, S.}},
  issn         = {{2158-3188}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Translational Psychiatry}},
  title        = {{The effect of citalopram treatment on amyloid-β precursor protein processing and oxidative stress in human hNSC-derived neurons}},
  url          = {{http://dx.doi.org/10.1038/s41398-022-02050-5}},
  doi          = {{10.1038/s41398-022-02050-5}},
  volume       = {{12}},
  year         = {{2022}},
}