NTRK1 knockdown induces mouse cognitive impairment and hippocampal neuronal damage through mitophagy suppression via inactivating the AMPK/ULK1/FUNDC1 pathway.
Journal
Cell death discovery
ISSN: 2058-7716
Titre abrégé: Cell Death Discov
Pays: United States
ID NLM: 101665035
Informations de publication
Date de publication:
31 Oct 2023
31 Oct 2023
Historique:
received:
01
06
2023
accepted:
13
10
2023
revised:
03
10
2023
medline:
1
11
2023
pubmed:
1
11
2023
entrez:
1
11
2023
Statut:
epublish
Résumé
Hippocampal neuronal damage may induce cognitive impairment. Neurotrophic tyrosine kinase receptor 1 (NTRK1) reportedly regulates neuronal damage, although the underlying mechanism remains unclear. The present study aimed to investigate the role of NTRK1 in mouse hippocampal neuronal damage and the specific mechanism. A mouse NTRK1-knockdown model was established and subjected to pre-treatment with BAY-3827, followed by a behavioral test, Nissl staining, and NeuN immunofluorescence (IF) staining to evaluate the cognitive impairment and hippocampal neuronal damage. Next, an in vitro analysis was conducted using the CCK-8 assay, TUNEL assay, NeuN IF staining, DCFH-DA staining, JC-1 staining, ATP content test, mRFP-eGFP-LC3 assay, and LC3-II IF staining to elucidate the effect of NTRK1 on mouse hippocampal neuronal activity, apoptosis, damage, mitochondrial function, and autophagy. Subsequently, rescue experiments were performed by subjecting the NTRK1-knockdown neurons to pre-treatment with O304 and Rapamycin. The AMPK/ULK1/FUNDC1 pathway activity and mitophagy were detected using western blotting (WB) analysis. Resultantly, in vivo analysis revealed that NTRK1 knockdown induced mouse cognitive impairment and hippocampal tissue damage, in addition to inactivating the AMPK/ULK1/FUNDC1 pathway activity and mitophagy in the hippocampal tissues of mice. The treatment with BAY-3827 exacerbated the mouse depressive-like behavior induced by NTRK1 knockdown. The results of in vitro analysis indicated that NTRK1 knockdown attenuated viability, NeuN expression, ATP production, mitochondrial membrane potential, and mitophagy, while enhancing apoptosis and ROS production in mouse hippocampal neurons. Conversely, pre-treatment with O304 and rapamycin abrogated the suppression of mitophagy and the promotion of neuronal damage induced upon NTRK1 silencing. Conclusively, NTRK1 knockdown induces mouse hippocampal neuronal damage through the suppression of mitophagy via inactivating the AMPK/ULK1/FUNDC1 pathway. This finding would provide insight leading to the development of novel strategies for the treatment of cognitive impairment induced due to hippocampal neuronal damage.
Identifiants
pubmed: 37907480
doi: 10.1038/s41420-023-01685-7
pii: 10.1038/s41420-023-01685-7
pmc: PMC10618268
doi:
Types de publication
Journal Article
Langues
eng
Pagination
404Subventions
Organisme : Beijing Nova Program
ID : Z201100006820057
Informations de copyright
© 2023. The Author(s).
Références
Front Cell Dev Biol. 2021 Dec 16;9:788634
pubmed: 35096821
Transl Psychiatry. 2020 Nov 24;10(1):407
pubmed: 33235206
J Inflamm Res. 2021 Dec 30;14:7501-7506
pubmed: 35002283
Cell Prolif. 2020 Oct;53(10):e12912
pubmed: 32964544
Front Immunol. 2021 Feb 24;12:628168
pubmed: 33717152
Neurochem Res. 2023 Sep;48(9):2595-2606
pubmed: 37097395
J Stroke Cerebrovasc Dis. 2023 Feb;32(2):106923
pubmed: 36521373
Brain Res Bull. 2022 Nov;190:84-96
pubmed: 36174874
Int J Mol Sci. 2021 May 03;22(9):
pubmed: 34063708
Mol Genet Genomic Med. 2021 Nov;9(11):e1839
pubmed: 34674383
Biomed Res Int. 2015;2015:857202
pubmed: 26509167
Exp Ther Med. 2016 Jun;11(6):2240-2246
pubmed: 27284307
Front Behav Neurosci. 2021 May 05;15:623644
pubmed: 34025367
Trends Neurosci. 2022 Apr;45(4):312-322
pubmed: 35249745
J Comp Neurol. 2022 Dec;530(17):2977-2993
pubmed: 35844047
Oxid Med Cell Longev. 2022 Jul 13;2022:5757367
pubmed: 35873803
Brain Res. 2020 Nov 1;1746:147018
pubmed: 32679115
J Neurochem. 2010 Feb;112(4):882-99
pubmed: 19943845
Immunopharmacol Immunotoxicol. 2022 Oct;44(5):766-772
pubmed: 35620829
Neuron. 2022 Mar 16;110(6):967-976.e8
pubmed: 35051374
Redox Biol. 2021 Jan;38:101792
pubmed: 33212415
Sheng Li Xue Bao. 2020 Oct 25;72(5):631-642
pubmed: 33106833
Hippocampus. 2011 Apr;21(4):446-59
pubmed: 20054812
Environ Pollut. 2020 Jun;261:114207
pubmed: 32220751
J Neuroinflammation. 2021 Sep 16;18(1):207
pubmed: 34530866
Exp Mol Pathol. 2021 Dec;123:104679
pubmed: 34481839
Phytomedicine. 2022 Jun;100:154056
pubmed: 35338989
Neurochem Res. 2018 Aug;43(8):1539-1548
pubmed: 29923038
Clin Auton Res. 2002 May;12 Suppl 1:I20-32
pubmed: 12102460
Front Genet. 2021 Dec 06;12:763467
pubmed: 34938316
Sci Rep. 2021 Sep 15;11(1):18338
pubmed: 34526554
Brain Res. 2015 Oct 5;1622:186-95
pubmed: 26133793
J Physiol Sci. 2022 Nov 22;72(1):29
pubmed: 36418941
Mol Aspects Med. 2021 Dec;82:100972
pubmed: 34130867
Biomedicines. 2022 Oct 27;10(11):
pubmed: 36359242
Neurochem Res. 2023 May;48(5):1504-1515
pubmed: 36512295
Appl Immunohistochem Mol Morphol. 2021 Jul 1;29(6):e46-e56
pubmed: 33710124
Redox Biol. 2020 Feb;30:101415
pubmed: 31901590
Toxicology. 2023 Mar 15;487:153461
pubmed: 36805303
Pharm Biol. 2023 Dec;61(1):271-280
pubmed: 36655371
Neurochem Res. 2023 Jan;48(1):284-294
pubmed: 36094682
Cell Death Dis. 2022 May 9;13(5):444
pubmed: 35534453
ESMO Open. 2016 Mar 18;1(2):e000023
pubmed: 27843590
Cell Death Dis. 2021 Oct 7;12(10):917
pubmed: 34620841
Oncogene. 2018 May;37(20):2714-2727
pubmed: 29507419
Metabolites. 2022 Dec 01;12(12):
pubmed: 36557245
Trends Mol Med. 2020 Jan;26(1):8-20
pubmed: 31375365
J Biol Chem. 2016 Oct 7;291(41):21363-21374
pubmed: 27551041
ACS Chem Neurosci. 2021 Jul 7;12(13):2280-2307
pubmed: 33843209
J Hazard Mater. 2021 Jun 5;411:125179
pubmed: 33858114
Nat Rev Mol Cell Biol. 2018 Feb;19(2):121-135
pubmed: 28974774
Food Chem Toxicol. 2017 Nov;109(Pt 1):505-516
pubmed: 28974442