TonEBP Haploinsufficiency Attenuates Microglial Activation and Memory Deficits in Middle-Aged and Amyloid β Oligomer-Treated Mice.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Amyloid beta-Peptides*/metabolism ; NFATC Transcription Factors*/metabolism; Animals ; Mice ; Haploinsufficiency ; Memory Disorders/metabolism ; Microglia/metabolism

Age-related microglial activation is associated with cognitive impairment. Tonicity-responsive enhancer-binding protein (TonEBP) is a critical mediator of microglial activation in response to neuroinflammation. However, the precise role of TonEBP in the middle-aged brain is not yet known. We used TonEBP haploinsufficient mice to investigate the role of TonEBP in middle-aged or amyloid β oligomer (AβO)-injected brains and examined the effect of TonEBP knockdown on AβO-treated BV2 microglial cells. Consistent with an increase in microglial activation with aging, hippocampal TonEBP expression levels were increased in middle-aged (12-month-old) and old (24-month-old) mice compared with young (6-month-old) mice. Middle-aged TonEBP haploinsufficient mice showed reduced microglial activation and fewer memory deficits than wild-type mice. Electron microscopy revealed that synaptic pruning by microglial processes was reduced by TonEBP haploinsufficiency. TonEBP haploinsufficiency also reduced dendritic spine loss and improved memory deficits in AβO-treated mice. Furthermore, TonEBP knockdown attenuated migration and phagocytosis in AβO-treated BV2 cells. These findings suggest that TonEBP plays important roles in age-related microglial activation and memory deficits.

Aging Cell. 2014 Aug;13(4):605-15. (PMID: 24621265)
Neuron. 2013 Jan 9;77(1):10-8. (PMID: 23312512)
Neurobiol Aging. 2018 Nov;71:91-104. (PMID: 30118927)
Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2538-42. (PMID: 10051678)
Neurosci Lett. 2015 Aug 5;601:30-40. (PMID: 25578949)
Sci Rep. 2017 Sep 11;7(1):11118. (PMID: 28894284)
Diabetes. 2012 Jun;61(6):1444-54. (PMID: 22362175)
Neuron. 2013 Apr 10;78(1):94-108. (PMID: 23583109)
J Neuroinflammation. 2021 Nov 29;18(1):278. (PMID: 34844610)
Cell Death Dis. 2021 May 5;12(5):445. (PMID: 33953167)
J Vis Exp. 2017 May 28;(123):. (PMID: 28605382)
Front Aging Neurosci. 2017 Jan 31;9:8. (PMID: 28197095)
Science. 2011 Sep 9;333(6048):1456-8. (PMID: 21778362)
Ann Clin Lab Sci. 2019 Mar;49(2):249-256. (PMID: 31028072)
Nat Commun. 2014 Jul 22;5:4486. (PMID: 25047355)
Nat Rev Neurosci. 2016 Apr;17(4):201-7. (PMID: 26911435)
J Vis Exp. 2016 Mar 16;(109):. (PMID: 27023127)
Neural Plast. 2013;2013:425845. (PMID: 24392228)
Cell. 2015 Mar 12;160(6):1061-71. (PMID: 25728668)
J Neuroimmunol. 2016 Jun 15;295-296:21-9. (PMID: 27235345)
Trends Neurosci. 2013 Apr;36(4):209-17. (PMID: 23260014)
J Neuroinflammation. 2018 Aug 11;15(1):224. (PMID: 30098604)
Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2392-7. (PMID: 14983020)
Annu Rev Immunol. 2002;20:825-52. (PMID: 11861619)
J Neuroimmunol. 2016 Feb 15;291:115-24. (PMID: 26857505)
Mol Neurodegener. 2017 Aug 2;12(1):56. (PMID: 28768545)
J Cereb Blood Flow Metab. 2018 Nov;38(11):1885-1895. (PMID: 29135331)
Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10075-8. (PMID: 1359534)
Brain Behav Immun. 2016 Jan;51:230-239. (PMID: 26336035)
Expert Opin Investig Drugs. 1999 Oct;8(10):1521-1536. (PMID: 11139808)
Cell Rep. 2022 Jun 14;39(11):110961. (PMID: 35705056)
Cell Death Differ. 2014 Jul;21(7):1095-106. (PMID: 24608792)
J Neuroinflammation. 2021 Nov 6;18(1):258. (PMID: 34742308)
J Neurochem. 1998 Nov;71(5):2123-31. (PMID: 9798938)
J Neuroinflammation. 2018 Apr 14;15(1):107. (PMID: 29655369)
Glia. 1993 Jan;7(1):60-7. (PMID: 8423063)
Cell. 2007 Dec 14;131(6):1164-78. (PMID: 18083105)
Ageing Res Rev. 2020 Dec;64:101045. (PMID: 32171784)
J Neuroinflammation. 2020 Dec 8;17(1):372. (PMID: 33292328)
Sci Transl Med. 2014 Jul 2;6(243):243ra86. (PMID: 24990881)
Sci Rep. 2017 Aug 10;7(1):7837. (PMID: 28798347)
J Neuroimmune Pharmacol. 2013 Sep;8(4):807-23. (PMID: 23881706)
Trends Neurosci. 2010 Mar;33(3):121-9. (PMID: 20138375)
Curr Neuropharmacol. 2010 Mar;8(1):62-8. (PMID: 20808546)
Life Sci. 2016 Sep 15;161:37-44. (PMID: 27477351)
Front Immunol. 2019 Feb 19;10:270. (PMID: 30873159)
Front Cell Neurosci. 2018 Apr 19;12:106. (PMID: 29725290)
Int J Mol Sci. 2021 Aug 23;22(16):. (PMID: 34445767)

2021R1A2C2093913 National Research Foundation of Korea; RS-2023-00219399 National Research Foundation of Korea

Keywords: TonEBP; aging; amyloid beta; hippocampus; microglia

0 (Amyloid beta-Peptides)
0 (NFATC Transcription Factors)
0 (Nfat5 protein, mouse)

Date Created: 20231124 Date Completed: 20231128 Latest Revision: 20240201

20240202

PMC10670066

10.3390/cells12222612

37998347