Mimicking Age-Associated Gadd45γ Dysregulation Results in Memory Impairments in Young Adult Mice.
Gadd45g
MAPK signaling
activity-regulated transcription
aging-dependent cognitive decline
synapse-to-nucleus communication
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
ISSN: 1529-2401
Titre abrégé: J Neurosci
Pays: United States
ID NLM: 8102140
Informations de publication
Date de publication:
05 02 2020
05 02 2020
Historique:
received:
09
07
2019
revised:
08
11
2019
accepted:
05
12
2019
pubmed:
13
12
2019
medline:
18
8
2020
entrez:
13
12
2019
Statut:
ppublish
Résumé
Age-related memory loss is observed across multiple mammalian species and preferentially affects hippocampus-dependent memory. Memory impairments are characterized by accelerated decay of spatial memories. Nevertheless, the molecular mechanisms underlying these deficits are still largely unknown. Here, we investigated the expression and function of the growth arrest DNA damage (Gadd45) family during aging and cognition, respectively. We report that aging impairs the expression of Gadd45γ in the hippocampus of cognitively impaired male mice. Mimicking this decrease in young adult male mice led to age-like memory deficits in hippocampus-dependent memory tasks. Gadd45γ reduction impaired the activity of key components of the mitogen-activated protein kinase (MAPK) pathway (p38 and JNK) in mouse hippocampal cultures. Furthermore, we found that activation of downstream targets, such as ATF-2, c-Jun, and CREB (cAMP response element-binding protein), was disrupted. Finally, we showed that Gadd45γ is required for induction of key early- and late-response genes that have been associated with aging. Together, these findings indicate that Gadd45γ expression regulates cognitive abilities and synapse-to-nucleus communication and suggest Gadd45γ dysfunction as a potential mechanism contributing to age-related cognitive impairments.
Identifiants
pubmed: 31826946
pii: JNEUROSCI.1621-19.2019
doi: 10.1523/JNEUROSCI.1621-19.2019
pmc: PMC7002144
doi:
Substances chimiques
Cell Cycle Proteins
0
Gadd45a protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1197-1210Informations de copyright
Copyright © 2020 the authors.
Références
Elife. 2016 Mar 24;5:
pubmed: 27011354
J Neurosci. 2010 Oct 6;30(40):13348-61
pubmed: 20926661
Nat Neurosci. 2012 Jul 01;15(8):1111-3
pubmed: 22751036
Learn Mem. 2012 Jul 16;19(8):319-24
pubmed: 22802593
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
Alzheimers Dement (Amst). 2017 Apr 20;8:51-59
pubmed: 28492059
Behav Brain Res. 2017 Mar 30;322(Pt B):206-211
pubmed: 27478142
Biofactors. 2011 May-Jun;37(3):168-74
pubmed: 21698696
Exp Gerontol. 2003 Jan-Feb;38(1-2):61-9
pubmed: 12543262
J Biol Chem. 2015 Sep 18;290(38):23039-49
pubmed: 26231212
Neuron. 2007 Feb 15;53(4):549-62
pubmed: 17296556
Neuroreport. 2003 Oct 27;14(15):1989-92
pubmed: 14561935
Front Aging Neurosci. 2019 Jun 07;11:128
pubmed: 31231204
Ageing Res Rev. 2012 Jan;11(1):51-66
pubmed: 21986581
Nat Rev Neurosci. 2006 Jan;7(1):30-40
pubmed: 16371948
J Signal Transduct. 2012;2012:649079
pubmed: 22792454
Cell Rep. 2017 Jan 3;18(1):122-135
pubmed: 28052243
Curr Mol Med. 2012 Jun;12(5):634-51
pubmed: 22515981
Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5280-5
pubmed: 10220457
Elife. 2017 Jan 04;6:
pubmed: 28051768
Cell. 1998 Nov 13;95(4):521-30
pubmed: 9827804
Neuropsychopharmacology. 2012 Jan;37(2):531-42
pubmed: 22048458
J Neurosci. 2011 Mar 2;31(9):3295-308
pubmed: 21368041
eNeuro. 2015 Oct 15;2(5):null
pubmed: 26473169
Nat Neurosci. 2014 Oct;17(10):1330-9
pubmed: 25195102
J Neurosci. 2019 Feb 6;39(6):970-983
pubmed: 30545945
Front Aging Neurosci. 2011 May 25;3:9
pubmed: 21647305
J Neurosci. 2003 Aug 13;23(19):7317-25
pubmed: 12917365
Physiol Rev. 2009 Jan;89(1):121-45
pubmed: 19126756
Trends Neurosci. 2010 May;33(5):230-40
pubmed: 20223527
J Neurosci. 2012 Nov 28;32(48):17059-66
pubmed: 23197699
Front Aging Neurosci. 2012 Sep 12;4:12
pubmed: 22988436
Nat Rev Neurosci. 2014 May;15(5):285-99
pubmed: 24739785
Eur J Neurosci. 2003 Feb;17(4):897-902
pubmed: 12603281
Gene Ther. 2001 Sep;8(17):1323-32
pubmed: 11571569
J Mol Biol. 2008 Apr 18;378(1):97-111
pubmed: 18343408
Learn Mem. 2013 Sep 16;20(10):540-52
pubmed: 24042850
Mol Psychiatry. 2016 Aug;21(8):1130-6
pubmed: 26598069
J Neurosci. 2018 Apr 11;38(15):3708-3728
pubmed: 29540552
Science. 2009 Feb 20;323(5917):1074-7
pubmed: 19119186
Transl Psychiatry. 2019 Feb 14;9(1):89
pubmed: 30765688
Front Aging Neurosci. 2012 Sep 12;4:15
pubmed: 22988437
Science. 1991 Aug 23;253(5022):912-4
pubmed: 1715095
Neurobiol Learn Mem. 2018 Mar;149:84-97
pubmed: 29438740
PLoS Genet. 2009 Aug;5(8):e1000604
pubmed: 19680447
Cell. 2004 Dec 29;119(7):1041-54
pubmed: 15620361
Front Cell Neurosci. 2014 Nov 13;8:373
pubmed: 25431548
BMJ. 2012 Jan 05;344:d7622
pubmed: 22223828
Cell Rep. 2018 Jan 30;22(5):1124-1131
pubmed: 29386101
Cereb Cortex. 2017 Aug 1;27(8):4166-4181
pubmed: 28444170