Mitochondria modulatory effects of new TSPO ligands in a cellular model of tauopathies
© 2019 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology..
Translocator protein 18 kDa (TSPO) is a mitochondrial protein located in the outer membrane and involved in cholesterol translocation, a prerequisite for steroid biosynthesis. TSPO modulation also appears to play a role in other mitochondrial functions, including mitochondrial respiration and cell survival. In the central nervous system, its expression is up-regulated in neuropathology such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands, named 2a and 2b, stimulated pregnenolone synthesis and ATP production in a cellular model of AD overproducing β-amyloid peptide. The present study aimed to evaluate the impact of the new TSPO ligands on mitochondrial dysfunction in a cellular model of AD-related tauopathy (human neuroblastoma cells SH-SY5Y stably overexpressing the P301L-mutant Tau) presenting mitochondrial impairments, including a decreased ATP synthesis and mitochondrial membrane potential, as well as a decrease in pregnenolone synthesis compared to control cells. The effects of our new ligands were compared with those of TSPO ligands described in the literature (XBD173, SSR-180,575 and Ro5-4864). The TSPO ligands 2a and 2b exerted beneficial mitochondrial modulatory effects by increasing ATP levels and mitochondrial membrane potential, paralleled by an increase of pregnenolone levels in mutant Tau cells, as well as in control cells. The compounds 2a and 2b showed effects on mitochondrial activity similar to those obtained with the TSPO ligands of reference. These findings indicate that the new TSPO ligands modulate the mitochondrial bioenergetic phenotype as well as the de novo synthesis of neurosteroids in a cellular model of AD-related tauopathy, suggesting that these compounds could be potential new therapeutic tools for the treatment of AD.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:32 |
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| Enthalten in: |
Journal of neuroendocrinology - 32(2020), 1 vom: 01. Jan., Seite e12796 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Grimm, Amandine [VerfasserIn] |
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| Links: |
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| Themen: |
Alzheimer's disease |
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| Anmerkungen: |
Date Completed 26.05.2021 Date Revised 26.05.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/jne.12796 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a © 2019 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology. | ||
| 520 | |a Translocator protein 18 kDa (TSPO) is a mitochondrial protein located in the outer membrane and involved in cholesterol translocation, a prerequisite for steroid biosynthesis. TSPO modulation also appears to play a role in other mitochondrial functions, including mitochondrial respiration and cell survival. In the central nervous system, its expression is up-regulated in neuropathology such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands, named 2a and 2b, stimulated pregnenolone synthesis and ATP production in a cellular model of AD overproducing β-amyloid peptide. The present study aimed to evaluate the impact of the new TSPO ligands on mitochondrial dysfunction in a cellular model of AD-related tauopathy (human neuroblastoma cells SH-SY5Y stably overexpressing the P301L-mutant Tau) presenting mitochondrial impairments, including a decreased ATP synthesis and mitochondrial membrane potential, as well as a decrease in pregnenolone synthesis compared to control cells. The effects of our new ligands were compared with those of TSPO ligands described in the literature (XBD173, SSR-180,575 and Ro5-4864). The TSPO ligands 2a and 2b exerted beneficial mitochondrial modulatory effects by increasing ATP levels and mitochondrial membrane potential, paralleled by an increase of pregnenolone levels in mutant Tau cells, as well as in control cells. The compounds 2a and 2b showed effects on mitochondrial activity similar to those obtained with the TSPO ligands of reference. These findings indicate that the new TSPO ligands modulate the mitochondrial bioenergetic phenotype as well as the de novo synthesis of neurosteroids in a cellular model of AD-related tauopathy, suggesting that these compounds could be potential new therapeutic tools for the treatment of AD | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Alzheimer's disease | |
| 650 | 4 | |a TSPO ligands | |
| 650 | 4 | |a Tau protein | |
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| 700 | 1 | |a Hallé, François |e verfasserin |4 aut | |
| 700 | 1 | |a Schmitt, Martine |e verfasserin |4 aut | |
| 700 | 1 | |a Götz, Jürgen |e verfasserin |4 aut | |
| 700 | 1 | |a Bihel, Frederic |e verfasserin |4 aut | |
| 700 | 1 | |a Eckert, Anne |e verfasserin |4 aut | |
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