Kallistatin leads to cognition impairment via downregulating glutamine synthetase
Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved..
In many neurodegenerative disorders, such as Alzheimer's disease (AD), glutamate-mediated neuronal excitotoxicity is considered the basis for cognitive impairment. The mRNA and protein expression of SERPINA4(Kallistatin) are higher in patients with AD. However, whether Kallistatin plays a regulatory role in glutamate-glutamine cycle homeostasis remains unclear. In this study, we identified impaired cognitive function in Kallistatin transgenic (KAL-TG) mice. Baseline glutamate levels were elevated and miniature excitatory postsynaptic current (mEPSC) frequency was increased in the hippocampus, suggesting the impairment of glutamate homeostasis in KAL-TG mice. Mechanistically, we demonstrated that Kallistatin promoted lysine acetylation and ubiquitination of glutamine synthetase (GS) and facilitated its degradation via the proteasome pathway, thereby downregulating GS. Fenofibrate improved cognitive memory in KAL-TG mice by downregulating serum Kallistatin. Collectively, our study findings provide insights the mechanism by which Kallistatin regulates cognitive impairment, and suggest the potential of fenofibrate to prevente and treat of AD patients with high levels of Kallistatin.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:202 |
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| Enthalten in: |
Pharmacological research - 202(2024) vom: 16. März, Seite 107145 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Long, Yanlan [VerfasserIn] |
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| Links: |
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| Themen: |
3KX376GY7L |
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| Anmerkungen: |
Date Completed 27.03.2024 Date Revised 27.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.phrs.2024.107145 |
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| PPN (Katalog-ID): |
NLM369825055 |
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| 520 | |a In many neurodegenerative disorders, such as Alzheimer's disease (AD), glutamate-mediated neuronal excitotoxicity is considered the basis for cognitive impairment. The mRNA and protein expression of SERPINA4(Kallistatin) are higher in patients with AD. However, whether Kallistatin plays a regulatory role in glutamate-glutamine cycle homeostasis remains unclear. In this study, we identified impaired cognitive function in Kallistatin transgenic (KAL-TG) mice. Baseline glutamate levels were elevated and miniature excitatory postsynaptic current (mEPSC) frequency was increased in the hippocampus, suggesting the impairment of glutamate homeostasis in KAL-TG mice. Mechanistically, we demonstrated that Kallistatin promoted lysine acetylation and ubiquitination of glutamine synthetase (GS) and facilitated its degradation via the proteasome pathway, thereby downregulating GS. Fenofibrate improved cognitive memory in KAL-TG mice by downregulating serum Kallistatin. Collectively, our study findings provide insights the mechanism by which Kallistatin regulates cognitive impairment, and suggest the potential of fenofibrate to prevente and treat of AD patients with high levels of Kallistatin | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Xie, Wanting |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Jinhui |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Fengyu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Qilong |e verfasserin |4 aut | |
| 700 | 1 | |a Ti, Zhou |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Bin |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Xia |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Guoquan |e verfasserin |4 aut | |
| 700 | 1 | |a Qi, Weiwei |e verfasserin |4 aut | |
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