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Artemisinin-treatment in pre-symptomatic APP-PS1 mice increases gephyrin phosphorylation at Ser270: a modification regulating postsynaptic GABAAR density

Authors
  • Kiss, Eva1, 2
  • Kins, Stefan3
  • Gorgas, Karin1
  • Orlik, Maret1
  • Fischer, Carolin1
  • Endres, Kristina4
  • Schlicksupp, Andrea1
  • Kirsch, Joachim1
  • Kuhse, Jochen1
  • 1 University of Heidelberg, Im Neuenheimer Feld 307, D-69120 , (Germany)
  • 2 University of Medicine, Pharmacy, Science and Technology “G.E. Palade” of Târgu Mures, Str. Gheorghe Marinescu nr. 38, 540 139 , (Romania)
  • 3 Department of Human Biology and Human Genetics, University of Kaiserslautern, Germany , (Germany)
  • 4 Department of Psychiatry and Psychotherapy, University Medical Center Johannes Gutenberg-University Mainz, Germany , (Germany)
Type
Published Article
Journal
Biological Chemistry
Publisher
Walter de Gruyter GmbH
Publication Date
Apr 20, 2021
Volume
403
Issue
1
Pages
73–87
Identifiers
DOI: 10.1515/hsz-2021-0153
Source
De Gruyter
Keywords
License
Green

Abstract

Artemisinins, a group of plant-derived sesquiterpene lactones, are efficient antimalarial agents. They also share anti-inflammatory and anti-viral activities and were considered for treatment of neurodegenerative disorders like Alzheimer’s disease (AD). Additionally, artemisinins bind to gephyrin, the multifunctional scaffold of GABAergic synapses, and modulate inhibitory neurotransmission in vitro. We previously reported an increased expression of gephyrin and GABAA receptors in early pre-symptomatic stages of an AD mouse model (APP-PS1) and in parallel enhanced CDK5-dependent phosphorylation of gephyrin at S270. Here, we studied the effects of artemisinin on gephyrin in the brain of young APP-PS1 mice. We detected an additional increase of gephyrin protein level, elevated gephyrin phosphorylation at Ser270, and an increased amount of GABAAR-γ2 subunits after artemisinin-treatment. Interestingly, the CDK5 activator p35 was also upregulated. Moreover, we demonstrate decreased density of postsynaptic gephyrin and GABAAR-γ2 immunoreactivities in cultured hippocampal neurons expressing gephyrin with alanine mutations at two CDK5 phosphorylation sites. In addition, the activity-dependent modulation of synaptic protein density was abolished in neurons expressing gephyrin lacking one or both of these phosphorylation sites. Thus, our results reveal that artemisinin modulates expression as well as phosphorylation of gephyrin at sites that might have important impact on GABAergic synapses in AD.

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