title: The role of telomerase protein TERT in Alzheimer's disease and in tau-related pathology in vitro.
abstract: The telomerase reverse transcriptase protein TERT has recently been demonstrated to have a variety of functions both in vitro and in vivo, which are distinct from its canonical role in telomere extension. In different cellular systems, TERT protein has been shown to be protective through its interaction with mitochondria. TERT has previously been found in rodent neurons, and we hypothesize that it might have a protective function in adult human brain. Here, we investigated the expression of TERT at different stages of Alzheimer's disease pathology (Braak Stages I-VI) in situ and the ability of TERT to protect against oxidative damage in an in vitro model of tau pathology. Our data reveal that TERT is expressed in vitro in mouse neurons and microglia, and in vivo in the cytoplasm of mature human hippocampal neurons and activated microglia, but is absent from astrocytes. Intriguingly, hippocampal neurons expressing TERT did not contain hyperphosphorylated tau. Vice versa, neurons that expressed high levels of pathological tau did not appear to express TERT protein. TERT protein colocalized with mitochondria in the hippocampus of Alzheimer's disease brains (Braak Stage VI), as well as in cultured neurons under conditions of oxidative stress. Our in vitro data suggest that the absence of TERT increases ROS generation and oxidative damage in neurons induced by pathological tau. Together, our findings suggest that TERT protein persists in neurons of the adult human brain, where it may have a protective role against tau pathology.
authors: Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Institute for Cell and Molecular Bioscience, and.
authors: Alison
authors: A
authors: Spilsbury
authors: Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Institute for Cell and Molecular Bioscience, and.
authors: Satomi
authors: S
authors: Miwa
authors: Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors: Johannes
authors: J
authors: Attems
authors: Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Institute for Cell and Molecular Bioscience, and gabriele.saretzki@newcastle.ac.uk.
authors: Gabriele
authors: http://orcid.org/0000-0003-2100-8223
authors: G
authors: Saretzki
mesh_terms: D000293:Adolescent; D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004622:Embryo, Mammalian; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation / Q000235:genetics; D008099:Liver / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011180:Postmortem Changes; D024801:Tauopathies / Q000473:pathology*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D019098:Telomerase; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C509186:TERT protein, human
keywords: Alzheimer's disease; mitochondria; neuroprotection; oxidative stress; tau; telomerase
references: Acta Neuropathol. 2006 Oct;112(4):389-404
references: 16906426
references: Nat Commun. 2014;5:3837
references: 24815183
references: Acta Neuropathol Commun. 2014;2:14
references: 24479894
references: Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20057-62
references: 19897719
references: Childs Nerv Syst. 2002 Apr;18(3-4):112-7
references: 11981616
references: J Neurochem. 1997 May;68(5):2092-7
references: 9109537
references: Biochem Biophys Res Commun. 2012 Feb 17;418(3):578-83
references: 22293195
references: J Neurosci. 2002 Nov 15;22(22):9733-41
references: 12427828
references: Brain. 2009 May;132(Pt 5):1324-34
references: 19321462
references: Nat Rev Drug Discov. 2004 Mar;3(3):205-14
references: 15031734
references: Mol Cell Biol. 2003 Jul;23(13):4598-610
references: 12808100
references: Mol Cell Neurosci. 2012 Jan;49(1):44-53
references: 21945393
references: Science. 2012 Sep 21;337(6101):1488-92
references: 22997326
references: J Cell Sci. 2000 Nov;113 Pt 21:3737-45
references: 11034902
references: Acta Neuropathol. 2000 May;99(5):469-81
references: 10805089
references: Rejuvenation Res. 2012 Apr;15(2):206-9
references: 22533433
references: J Neurochem. 2000 Jul;75(1):117-24
references: 10854254
references: Neuromolecular Med. 2002;2(2):215-31
references: 12428812
references: Oncogene. 2008 Jun 12;27(26):3754-60
references: 18223679
references: Am J Pathol. 1999 Jan;154(1):255-70
references: 9916940
references: Proteomics Clin Appl. 2009 Jun 1;3(6):682-693
references: 20333275
references: PLoS One. 2009;4(10):e7280
references: 19794916
references: Neurobiol Aging. 2000 May-Jun;21(3):455-62
references: 10858595
references: PLoS One. 2011;6(12):e26860
references: 22174735
references: J Mol Neurosci. 2000 Feb-Apr;14(1-2):3-15
references: 10854032
references: Proc Natl Acad Sci U S A. 1986 Jul;83(13):4913-7
references: 3088567
references: Mol Ther. 2013 Jul;21(7):1358-68
references: 23609018
references: Nat Med. 1996 Jul;2(7):783-7
references: 8673924
references: Brain Res. 2011 Sep 30;1415:136-48
references: 21872849
references: Nature. 2006 Oct 19;443(7113):787-95
references: 17051205
references: Mol Cell Neurosci. 2003 Aug;23(4):693-702
references: 12932448
references: Acta Neuropathol. 2013 Dec;126(6):907-15
references: 24154961
references: Eur J Neurosci. 2006 Aug;24(4):1085-90
references: 16930434
references: J Neuropathol Exp Neurol. 2008 May;67(5):470-83
references: 18431250
references: Acta Neuropathol. 1996;91(6):633-41
references: 8781663
references: Nucleic Acids Res. 2007;35(22):7497-504
references: 17947327
references: Proc Natl Acad Sci U S A. 2014 Mar 25;111(12):4584-9
references: 24623856
references: Acta Neuropathol. 1995;89(4):291-5
references: 7610759
references: Nat Rev Neurosci. 2008 Jul;9(7):532-44
references: 18568014
references: Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10771-8
references: 7971961
references: Curr Pharm Des. 2014;20(41):6386-403
references: 24975608
references: Acta Neuropathol. 1991;82(4):239-59
references: 1759558
references: Exp Neurol. 2002 Dec;178(2):294-300
references: 12504888
references: J Neurosci. 2004 Feb 11;24(6):1280-7
references: 14960598
references: J Neurosci. 2009 Jul 15;29(28):9090-103
references: 19605646
references: Acta Neuropathol. 2009 Jul;118(1):5-36
references: 19381658
references: Acta Neuropathol. 2012 Jan;123(1):1-11
references: 22101365
references: J Biol Chem. 2005 Jun 24;280(25):23802-14
references: 15831501
references: FEBS Lett. 2006 Jun 26;580(15):3582-8
references: 16753151
references: J Alzheimers Dis. 2011;23(1):161-9
references: 20966551
references: Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):8229-34
references: 10393977
references: J Cell Sci. 2008 Apr 1;121(Pt 7):1046-53
references: 18334557
references: Neurology. 1991 Apr;41(4):479-86
references: 2011243
references: Nature. 1998 Jun 18;393(6686):702-5
references: 9641683
references: Nucleic Acids Res. 2012 Jan;40(2):712-25
references: 21937513
references: Eur J Cancer. 1997 Apr;33(5):787-91
references: 9282118
references: Mol Neurobiol. 2010 Jun;41(2-3):107-14
references: 20217279
references: Trends Neurosci. 1989 Mar;12(3):94-101
references: 2469224
references: Mitochondrion. 2007 Sep;7(5):297-310
references: 17625988
references: Neuron. 1993 Jul;11(1):153-63
references: 8393323
references: J Cereb Blood Flow Metab. 2001 Oct;21(10):1133-45
references: 11598490
references: PLoS One. 2007;2(6):e536
references: 17579710
references: J Neurosci. 2003 Apr 1;23(7):2557-63
references: 12684440
references: Ann Neurol. 2005 Oct;58(4):495-505
references: 16178023
references: J Neurochem. 1994 Dec;63(6):2179-84
references: 7964738
references: Cell Motil Cytoskeleton. 2008 Feb;65(2):89-99
references: 18000878
references: Neurochem Res. 2010 Feb;35(2):211-8
references: 19685288
references: J Proteomics. 2011 Apr 1;74(4):466-79
references: 21237293
references: J Neurosci Res. 2001 May 1;64(3):252-60
references: 11319769
references: Aging Cell. 2004 Dec;3(6):399-411
references: 15569357
references: J Cell Biochem. 2013 Feb;114(2):409-17
references: 22961627
references: J Neurosci. 2002 Dec 15;22(24):10710-9
references: 12486164
references: J Biol Chem. 2006 Jan 13;281(2):1205-14
references: 16246844
references: EMBO Mol Med. 2012 Apr;4(4):313-29
references: 22351600
references: PLoS One. 2013 Jun 18;8(6):e66602
references: 23825548
references: J Cell Biol. 2002 Mar 18;156(6):1051-63
references: 11901170
references: EMBO J. 1995 Apr 3;14(7):1304-13
references: 7729409
references: J Neurosci Res. 2005 Oct 15;82(2):160-71
references: 16175576
references: Mol Cell Biol. 2004 Aug;24(16):7024-31
references: 15282303
references: Science. 2001 Aug 24;293(5534):1491-5
references: 11520988
references: Nucleic Acids Res. 2013 Oct;41(19):8969-78
references: 23901009
references: Neurology. 2002 Jun 25;58(12):1791-800
references: 12084879
references: Arterioscler Thromb Vasc Biol. 2009 Jun;29(6):929-35
references: 19265030
references: Brain Res Dev Brain Res. 2001 Nov 26;131(1-2):167-71
references: 11718848
references: J Cell Biol. 1998 Nov 2;143(3):777-94
references: 9813097
references: PLoS One. 2013;8(1):e52989
references: 23326372
references: Dev Biol. 1997 May 1;185(1):82-91
references: 9169052
references: J Neurosci. 2005 Jun 1;25(22):5446-54
references: 15930395