Fate and propagation of endogenously formed Tau aggregates in neuronal cells.
Intercellular spreading
Tau aggregates
autophagy
prion-like seeding
tunneling nanotubes
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
07 12 2020
07 12 2020
Historique:
received:
14
01
2020
revised:
18
09
2020
accepted:
21
09
2020
pubmed:
13
11
2020
medline:
21
7
2021
entrez:
12
11
2020
Statut:
ppublish
Résumé
Tau accumulation in the form of neurofibrillary tangles in the brain is a hallmark of tauopathies such as Alzheimer's disease (AD). Tau aggregates accumulate in brain regions in a defined spatiotemporal pattern and may induce the aggregation of native Tau in a prion-like manner. However, the underlying mechanisms of cell-to-cell spreading of Tau pathology are unknown and could involve encapsulation within exosomes, trans-synaptic passage, and tunneling nanotubes (TNTs). We have established a neuronal cell model to monitor both internalization of externally added fibrils, synthetic (K18) or Tau from AD brain extracts, and real-time conversion of microtubule-binding domain of Tau fused to a fluorescent marker into aggregates. We found that these endogenously formed deposits colabel with ubiquitin and p62 but are not recruited to macroautophagosomes, eventually escaping clearance. Furthermore, endogenous K18-seeded Tau aggregates spread to neighboring cells where they seed new deposits. Transfer of Tau aggregates depends on direct cell contact, and they are found inside TNTs connecting neuronal cells. We further demonstrate that contact-dependent transfer occurs in primary neurons and between neurons and astrocytes in organotypic cultures.
Identifiants
pubmed: 33179866
doi: 10.15252/emmm.202012025
pmc: PMC7721367
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
Pagination
e12025Subventions
Organisme : EU Joint Programme - Neurodegenerative Disease Research (JPND)
Informations de copyright
© 2020 The Authors.
Références
J Biol Chem. 2009 May 8;284(19):12845-52
pubmed: 19282288
Nat Commun. 2017 Nov 22;8(1):1678
pubmed: 29162800
Neurobiol Dis. 2012 Dec;48(3):356-66
pubmed: 22668776
Expert Opin Investig Drugs. 2019 Jun;28(6):545-554
pubmed: 31094578
Invest Ophthalmol Vis Sci. 2017 Oct 1;58(12):5298-5307
pubmed: 29049733
J Biol Chem. 2015 Aug 28;290(35):21652-62
pubmed: 26126828
J Biol Chem. 2013 Jan 18;288(3):1856-70
pubmed: 23188818
Proc Natl Acad Sci U S A. 2017 Jan 17;114(3):574-579
pubmed: 28049840
EMBO Mol Med. 2020 Dec 7;12(12):e12025
pubmed: 33179866
Cell Rep. 2016 Oct 18;17(4):931-940
pubmed: 27760323
J Exp Med. 2016 Nov 14;213(12):2635-2654
pubmed: 27810929
Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):E4376-85
pubmed: 25261551
J Cell Sci. 2013 Oct 1;126(Pt 19):4424-35
pubmed: 23886947
Nature. 2018 Sep;561(7721):137-140
pubmed: 30158706
J Cell Biol. 2017 Sep 4;216(9):2633-2644
pubmed: 28724527
Acta Neuropathol Commun. 2016 Nov 4;4(1):117
pubmed: 27809932
J Cell Sci. 2018 Oct 5;131(19):
pubmed: 30209134
EMBO J. 2019 Dec 2;38(23):e101230
pubmed: 31625188
J Neuropathol Exp Neurol. 2005 Feb;64(2):113-22
pubmed: 15751225
Science. 2004 Feb 13;303(5660):1007-10
pubmed: 14963329
Brain. 2019 Jun 1;142(6):1736-1750
pubmed: 31038156
Am J Pathol. 2017 Jun;187(6):1399-1412
pubmed: 28408124
Curr Opin Cell Biol. 2016 Oct;42:63-72
pubmed: 27164504
EMBO J. 2018 Apr 3;37(7):
pubmed: 29472250
Acta Neuropathol Commun. 2020 Feb 4;8(1):13
pubmed: 32019610
Nat Cell Biol. 2009 Jul;11(7):909-13
pubmed: 19503072
Prog Neurobiol. 2013 Jun;105:49-59
pubmed: 23528736
Acta Neuropathol Commun. 2019 Aug 7;7(1):129
pubmed: 31391090
Sci Transl Med. 2011 Apr 6;3(77):77sr1
pubmed: 21471435
Nature. 2013 Sep 5;501(7465):45-51
pubmed: 24005412
J Neurosci. 2011 Sep 14;31(37):13110-7
pubmed: 21917794
Brain. 2017 Nov 1;140(11):2770-2773
pubmed: 29088348
Nat Commun. 2019 Jan 21;10(1):342
pubmed: 30664666
Front Mol Neurosci. 2017 Oct 17;10:333
pubmed: 29089870
Neurosci Lett. 1987 Aug 18;79(1-2):207-12
pubmed: 2823191
Acta Neuropathol Commun. 2014 Jan 30;2:14
pubmed: 24479894
EMBO J. 2016 Oct 4;35(19):2120-2138
pubmed: 27550960
EMBO J. 2017 Jan 17;36(2):135-150
pubmed: 27753622
Neuron. 2014 Jun 18;82(6):1271-88
pubmed: 24857020
Cell Stress. 2020 Jan 07;4(2):30-43
pubmed: 32043076
J Mol Cell Biol. 2017 Dec 1;9(6):516-532
pubmed: 28992183
Mol Brain. 2017 May 30;10(1):18
pubmed: 28558799
Science. 2015 Aug 7;349(6248):1255555
pubmed: 26250687
PLoS One. 2012;7(5):e36873
pubmed: 22615831
Prion. 2016 Sep 2;10(5):344-351
pubmed: 27715442
Trends Cancer. 2020 Oct;6(10):874-888
pubmed: 32471688
Sci Rep. 2016 Dec 23;6:39632
pubmed: 28008977
Acta Neuropathol. 2017 Nov;134(5):789-808
pubmed: 28725967
Biochemistry. 2006 Dec 26;45(51):15692-701
pubmed: 17176091
Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):E3138-47
pubmed: 23898162
FEBS Lett. 2013 Mar 18;587(6):717-23
pubmed: 23395797
Cell Death Differ. 2019 Aug;26(8):1411-1427
pubmed: 30442948
J Neuropathol Exp Neurol. 2011 Nov;70(11):960-9
pubmed: 22002422
J Biol Chem. 2019 Dec 13;294(50):18952-18966
pubmed: 31578281
Sci Rep. 2018 Apr 23;8(1):6382
pubmed: 29686391
Prion. 2009 Apr-Jun;3(2):94-8
pubmed: 19471116
Biochem Biophys Res Commun. 2018 Sep 18;503(4):2306-2311
pubmed: 29966650
Acta Neuropathol. 2018 Nov;136(5):819
pubmed: 30284035
J Biol Chem. 2016 Jun 17;291(25):13175-93
pubmed: 27129267
EMBO J. 2018 Mar 1;37(5):
pubmed: 29343546
Mol Neurodegener. 2020 Jan 6;15(1):2
pubmed: 31906970
Nature. 2017 Sep 20;549(7672):322-324
pubmed: 28933444
Neurobiol Dis. 2011 Jul;43(1):17-28
pubmed: 20732422
J Cell Sci. 2012 Mar 1;125(Pt 5):1089-98
pubmed: 22399801
Ann Neurol. 2011 Oct;70(4):532-40
pubmed: 22028219
J Cell Biol. 1998 Dec 28;143(7):1883-98
pubmed: 9864362
Curr Protoc Cell Biol. 2015 Jun 01;67:12.10.1-12.10.21
pubmed: 26061240
Acta Neuropathol. 1991;81(3):261-8
pubmed: 1711755
Neuron. 2012 Feb 23;73(4):685-97
pubmed: 22365544
Sci Transl Med. 2019 May 1;11(490):
pubmed: 31043574
J Biol Chem. 2009 Feb 6;284(6):3546-51
pubmed: 19010781
Cell Rep. 2015 May 26;11(8):1176-83
pubmed: 25981034
J Neurosci. 2017 Nov 22;37(47):11485-11494
pubmed: 28986461
Nat Commun. 2017 Aug 17;8(1):275
pubmed: 28819146
Mol Cell. 2018 Jan 18;69(2):214-226
pubmed: 29351843