Intraneuronal tau aggregation induces the integrated stress response in astrocytes.
antisense oligonucleotides
astrocytes
hiPSC-derived neurons
integrated stress response
oxidative stress
tau aggregation
Journal
Journal of molecular cell biology
ISSN: 1759-4685
Titre abrégé: J Mol Cell Biol
Pays: United States
ID NLM: 101503669
Informations de publication
Date de publication:
29 03 2023
29 03 2023
Historique:
received:
26
08
2022
revised:
27
09
2022
accepted:
13
12
2022
medline:
10
4
2023
pubmed:
16
12
2022
entrez:
15
12
2022
Statut:
ppublish
Résumé
Progressive aggregation of tau protein in neurons is associated with neurodegeneration in tauopathies. Cell non-autonomous disease mechanisms in astrocytes may be important drivers of the disease process but remain largely elusive. Here, we studied cell type-specific responses to intraneuronal tau aggregation prior to neurodegeneration. To this end, we developed a fully human co-culture model of seed-independent intraneuronal tau pathology, which shows no neuron and synapse loss. Using high-content microscopy, we show that intraneuronal tau aggregation induces oxidative stress accompanied by activation of the integrated stress response specifically in astrocytes. This requires the direct co-culture with neurons and is not related to neurodegeneration or extracellular tau levels. Tau-directed antisense therapy reduced intraneuronal tau levels and aggregation and prevented the cell non-autonomous responses in astrocytes. These data identify the astrocytic integrated stress response as a novel disease mechanism activated by intraneuronal tau aggregation. In addition, our data provide the first evidence for the efficacy of tau-directed antisense therapy to target cell autonomous and cell non-autonomous disease pathways in a fully human model of tau pathology.
Identifiants
pubmed: 36520068
pii: 6909069
doi: 10.1093/jmcb/mjac071
pmc: PMC10080549
pii:
doi:
Substances chimiques
tau Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© The Author(s) (2022). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.
Références
Neuron. 2013 Jun 5;78(5):785-98
pubmed: 23764284
Stem Cell Reports. 2020 Jul 14;15(1):38-51
pubmed: 32502466
Sci Transl Med. 2013 Oct 9;5(206):206ra138
pubmed: 24107777
Neurobiol Aging. 2009 Jan;30(1):1-13
pubmed: 17590238
EMBO Mol Med. 2020 Dec 7;12(12):e12025
pubmed: 33179866
J Exp Med. 2016 Nov 14;213(12):2635-2654
pubmed: 27810929
Sci Rep. 2016 Nov 07;6:36529
pubmed: 27819315
Neuron. 2016 Nov 23;92(4):796-812
pubmed: 27974162
Acta Neuropathol. 2015 Jun;129(6):875-94
pubmed: 25862635
Science. 2005 Jul 15;309(5733):476-81
pubmed: 16020737
J Neurosci. 2013 Aug 14;33(33):13300-11
pubmed: 23946388
Mol Neurodegener. 2017 Jun 29;12(1):50
pubmed: 28662669
Physiol Rev. 2018 Jan 1;98(1):239-389
pubmed: 29351512
J Neurochem. 2020 Jan;152(2):208-220
pubmed: 31442299
Glia. 2018 Apr;66(4):725-748
pubmed: 29230877
Nature. 2017 Jul 13;547(7662):185-190
pubmed: 28678775
Ann Neurol. 1997 Jan;41(1):17-24
pubmed: 9005861
Chemistry. 2015 Oct 19;21(43):15133-7
pubmed: 26388448
Cell Cycle. 2021 Apr;20(8):752-764
pubmed: 33818291
J Exp Med. 2019 Mar 4;216(3):539-555
pubmed: 30770411
Sci Transl Med. 2017 Jan 25;9(374):
pubmed: 28123067
Nat Commun. 2021 Jan 4;12(1):95
pubmed: 33398028
Annu Rev Neurosci. 2001;24:1121-59
pubmed: 11520930
Mol Psychiatry. 2021 Mar;26(3):784-799
pubmed: 31142819
Nat Neurosci. 2021 Mar;24(3):343-354
pubmed: 33558694
Acta Neuropathol. 2021 Mar;141(3):359-381
pubmed: 33496840
Nat Commun. 2017 May 02;8:15132
pubmed: 28462931
Nat Rev Neurosci. 2017 Jan;18(1):31-41
pubmed: 27904142
Nat Neurosci. 2019 Jan;22(1):47-56
pubmed: 30559469
Cell Rep. 2018 Aug 21;24(8):1939-1948.e4
pubmed: 30134156
J Biol Chem. 2018 Feb 16;293(7):2408-2421
pubmed: 29259137
EMBO Rep. 2013 Apr;14(4):389-94
pubmed: 23412472
Cell Rep. 2019 Aug 20;28(8):2111-2123.e6
pubmed: 31433986
Brain. 2021 May 7;144(4):1167-1182
pubmed: 33842937
Redox Biol. 2017 Aug;12:410-422
pubmed: 28319892
Nature. 2012 May 06;485(7399):507-11
pubmed: 22622579
Science. 2020 Apr 24;368(6489):
pubmed: 32327570
Acta Neuropathol. 2017 Feb;133(2):155-175
pubmed: 28025715
Nat Commun. 2022 Jan 10;13(1):135
pubmed: 35013236
Nat Neurosci. 2019 Dec;22(12):2087-2097
pubmed: 31768052
Cell Death Dis. 2015 Mar 05;6:e1672
pubmed: 25741597
Sci Rep. 2016 Apr 19;6:24544
pubmed: 27090093
PLoS One. 2015 Dec 31;10(12):e0146127
pubmed: 26720731
Mol Neurodegener. 2017 May 25;12(1):42
pubmed: 28545479
Neuron. 2020 Mar 4;105(5):855-866.e5
pubmed: 31924446
Aging Cell. 2018 Aug;17(4):e12775
pubmed: 29749079
Acta Neuropathol. 2019 Dec;138(6):943-970
pubmed: 31456031
Science. 1996 Apr 12;272(5259):263-7
pubmed: 8602510
Stem Cell Reports. 2016 Sep 13;7(3):325-340
pubmed: 27594585
Mol Cell. 2000 Nov;6(5):1099-108
pubmed: 11106749
Nat Rev Neurol. 2018 Jul;14(7):399-415
pubmed: 29895964
Alzheimers Dement. 2016 Jun;12(6):633-44
pubmed: 26776762
J Neurosci. 2015 Oct 21;35(42):14234-50
pubmed: 26490863
Dis Model Mech. 2020 Jan 17;13(1):
pubmed: 31953356
Chembiochem. 2019 Oct 1;20(19):2474-2478
pubmed: 31206961
Mol Neurobiol. 2016 Jan;53(1):648-661
pubmed: 25511446
Acta Neuropathol. 2015 Sep;130(3):315-31
pubmed: 26210990
Sci Rep. 2019 Feb 22;9(1):2587
pubmed: 30796247
Glia. 2017 Aug;65(8):1302-1316
pubmed: 28519902
EMBO J. 2022 Aug 16;41(16):e110501
pubmed: 35791631
J Am Chem Soc. 2012 Jun 20;134(24):10271-8
pubmed: 22656332
Sci Adv. 2021 Mar 19;7(12):
pubmed: 33741591
Brain. 2016 May;139(Pt 5):1551-67
pubmed: 26962052
J Vis Exp. 2017 Jan 8;(119):
pubmed: 28117798
Stem Cell Res. 2013 Sep;11(2):743-57
pubmed: 23759711
Front Cell Neurosci. 2021 Mar 17;15:645233
pubmed: 33815065
Acta Neuropathol Commun. 2017 Nov 29;5(1):89
pubmed: 29187256
Front Neurol. 2020 Sep 24;11:572850
pubmed: 33071951
Acta Neuropathol. 2015 Nov;130(5):633-42
pubmed: 26450683
Nat Commun. 2015 May 13;6:7066
pubmed: 25967870
Neuron. 2017 Feb 8;93(3):533-541.e5
pubmed: 28111080
Lancet Neurol. 2013 Jun;12(6):609-22
pubmed: 23684085
Brain. 2015 Nov;138(Pt 11):3345-59
pubmed: 26220942
J Biol Chem. 2009 Feb 6;284(6):3546-51
pubmed: 19010781
Cell Rep. 2015 May 26;11(8):1176-83
pubmed: 25981034
Annu Rev Pathol. 2019 Jan 24;14:239-261
pubmed: 30355155
Hum Mol Genet. 2019 Oct 1;28(19):3255-3269
pubmed: 31261380
Stem Cell Reports. 2015 Jul 14;5(1):83-96
pubmed: 26143746
Hum Mol Genet. 2015 Sep 15;24(18):5260-9
pubmed: 26136155