Mitochondria modulatory effects of new TSPO ligands in a cellular model of tauopathies.
Alzheimer's disease
TSPO ligands
Tau protein
bioenergetics
mitochondria
pregnenolone
Journal
Journal of neuroendocrinology
ISSN: 1365-2826
Titre abrégé: J Neuroendocrinol
Pays: United States
ID NLM: 8913461
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
15
04
2019
revised:
09
09
2019
accepted:
17
09
2019
pubmed:
20
9
2019
medline:
27
5
2021
entrez:
20
9
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31536662
doi: 10.1111/jne.12796
pmc: PMC7003898
doi:
Substances chimiques
Ligands
0
Receptors, GABA
0
TSPO protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12796Informations de copyright
© 2019 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.
Références
Oxid Med Cell Longev. 2015;2015:151979
pubmed: 26576216
Neuroscience. 2006;138(3):749-56
pubmed: 16338086
Mol Neurobiol. 2012 Aug;46(1):205-16
pubmed: 22847631
J Neuroendocrinol. 2016 Feb;28(2):12351
pubmed: 26681259
J Biol Chem. 2003 Oct 10;278(41):40162-8
pubmed: 12893817
Mol Neurobiol. 2012 Aug;46(1):151-60
pubmed: 22678467
Sci Rep. 2016 Jan 11;6:18164
pubmed: 26750656
J Neurosci. 2013 May 15;33(20):8891-7
pubmed: 23678130
Trends Endocrinol Metab. 2015 Jul;26(7):341-8
pubmed: 25801473
Eur J Pharm Sci. 2017 Jun 15;104:366-381
pubmed: 28435076
J Neurosci. 2005 May 11;25(19):4706-18
pubmed: 15888646
J Neurobiol. 2006 Jul;66(8):868-81
pubmed: 16673391
Prog Neurobiol. 2019 May;176:1-17
pubmed: 29981391
J Med Chem. 2008 Sep 25;51(18):5798-806
pubmed: 18729350
Neurosci Biobehav Rev. 2016 Aug;67:89-101
pubmed: 27139022
Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6498-503
pubmed: 20231471
Biochim Biophys Acta Mol Basis Dis. 2017 Mar;1863(3):631-642
pubmed: 27979708
Redox Biol. 2018 Sep;18:279-294
pubmed: 30077079
J Med Chem. 2004 Mar 25;47(7):1852-5
pubmed: 15027878
J Alzheimers Dis. 2019;72(4):1045-1058
pubmed: 31256132
Curr Alzheimer Res. 2012 May;9(4):473-80
pubmed: 22272610
Biol Reprod. 2011 May;84(5):976-85
pubmed: 21228212
Nat Rev Drug Discov. 2010 Dec;9(12):971-88
pubmed: 21119734
Front Neurosci. 2012 Feb 08;6:10
pubmed: 22347156
J Neuroendocrinol. 2020 Jan;32(1):e12796
pubmed: 31536662
Int J Mol Sci. 2016 Jun 29;17(7):
pubmed: 27367681
Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20057-62
pubmed: 19897719
Antioxid Redox Signal. 2012 Jun 15;16(12):1456-66
pubmed: 22117646
Bioorg Med Chem. 2001 Oct;9(10):2661-71
pubmed: 11557354
Biochim Biophys Acta. 2010 Aug;1801(8):951-9
pubmed: 20488256
J Biol Chem. 2005 Jun 24;280(25):23802-14
pubmed: 15831501
Cell Mol Life Sci. 2016 Jan;73(1):201-15
pubmed: 26198711
J Med Chem. 2012 May 10;55(9):4506-10
pubmed: 22489952
Eur J Med Chem. 2017 Jan 5;125:1172-1192
pubmed: 27855359
Nat Rev Endocrinol. 2013 Apr;9(4):241-50
pubmed: 23438839
Biochem Pharmacol. 2002 Jul 1;64(1):99-107
pubmed: 12106610
Biochim Biophys Acta. 2014 Dec;1842(12 Pt A):2427-38
pubmed: 25281013
Cell Mol Life Sci. 2019 Apr;76(7):1419-1431
pubmed: 30683981
Science. 2009 Jul 24;325(5939):490-3
pubmed: 19541954
Front Endocrinol (Lausanne). 2012 Jan 12;2:117
pubmed: 22654847
Biol Chem. 2010 Jun;391(6):619-29
pubmed: 20370325
J Med Chem. 1996 Aug 30;39(18):3435-50
pubmed: 8784441