title: Hyperphosphorylation-induced tau oligomers.
abstract: In normal adult brain the microtubule associated protein (MAP) tau contains 2-3 phosphates per mol of the protein and at this level of phosphorylation it is a soluble cytosolic protein. The normal brain tau interacts with tubulin and promotes its assembly into microtubules and stabilizes these fibrils. In Alzheimer disease (AD) brain tau is three to fourfold hyperphosphorylated. The abnormally hyperphosphorylated tau binds to normal tau instead of the tubulin and this binding leads to the formation of tau oligomers. The tau oligomers can be sedimented at 200,000 × g whereas the normal tau under these conditions remains in the supernatant. The abnormally hyperphosphorylated tau is capable of sequestering not only normal tau but also MAP MAP1 and MAP2 and causing disruption of the microtubule network promoted by these proteins. Unlike Aβ and prion protein (PrP) oligomers, tau oligomerization in AD and related tauopathies is hyperphosphorylation-dependent; in vitro dephosphorylation of AD P-tau with protein phosphatase 2A (PP2A) inhibits and rehyperphosphorylation of the PP2A-AD P-tau with more than one combination of tau protein kinases promotes its oligomerization. In physiological assembly conditions the AD P-tau readily self-assembles into paired helical filaments. Missense tau mutations found in frontotemporal dementia apparently lead to tau oligomerization and neurofibrillary pathology by promoting its abnormal hyperphosphorylation. Dysregulation of the alternative splicing of tau that alters the 1:1 ratio of the 3-repeat: 4-repeat taus such as in Down syndrome, Pick disease, and progressive supranuclear palsy leads to the abnormal hyperphosphorylation of tau.
authors: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities , Staten Island, NY , USA.
authors: Khalid
authors: K
authors: Iqbal
authors: Cheng-Xin
authors: CX
authors: Gong
authors: Fei
authors: F
authors: Liu
keywords: Alzheimer disease; Alzheimer neurofibrillary degeneration; O-GlcNAcylation of tau; abnormal hyperphosphorylation of tau; alternate splicing of tau; microtubule associated protein tau; protein phosphatase 2A; tauopathies
references: Nat Med. 1996 Aug;2(8):871-5
references: 8705855
references: J Neurochem. 1992 Aug;59(2):750-3
references: 1629745
references: Neuropathol Appl Neurobiol. 1987 Mar-Apr;13(2):91-110
references: 3614544
references: Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10804-9
references: 15249677
references: Arch Biochem Biophys. 1998 Sep 15;357(2):299-309
references: 9735171
references: Ann Neurol. 1998 Jun;43(6):815-25
references: 9629852
references: J Virol. 1996 Mar;70(3):1714-22
references: 8627692
references: Psychiatry Clin Neurosci. 1996 Jun;50(3):137-40
references: 9201760
references: Neuropathology. 2006 Oct;26(5):457-70
references: 17080726
references: J Alzheimers Dis. 2008 Apr;13(3):295-302
references: 18430997
references: Science. 2005 Jul 15;309(5733):476-81
references: 16020737
references: Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9670-4
references: 7937870
references: J Neurochem. 1995 Feb;64(2):777-87
references: 7830071
references: Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53
references: 9600986
references: Eur J Neurosci. 2007 Jan;25(1):59-68
references: 17241267
references: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6923-8
references: 11381127
references: Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5562-6
references: 8202528
references: FASEB J. 2010 Nov;24(11):4420-32
references: 20651003
references: Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17669-74
references: 22988095
references: J Biol Chem. 1995 Mar 3;270(9):4854-60
references: 7876258
references: FASEB J. 2008 Sep;22(9):3224-33
references: 18509201
references: Amino Acids. 2011 Mar;40(3):857-68
references: 20706749
references: J Neurocytol. 2003 Nov;32(9):1091-105
references: 15044841
references: Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):10032-7
references: 12888622
references: J Biol Chem. 2012 Jun 8;287(24):20711-9
references: 22539343
references: Lancet. 1986 Aug 23;2(8504):421-6
references: 2874414
references: FEBS Lett. 2005 Jan 17;579(2):363-72
references: 15642345
references: Brain. 2009 Jul;132(Pt 7):1820-32
references: 19451179
references: J Neuropathol Exp Neurol. 2007 Jan;66(1):17-25
references: 17204933
references: Nat Chem Biol. 2012 Feb 26;8(4):393-9
references: 22366723
references: J Biol Chem. 2008 Oct 17;283(42):28660-9
references: 18658135
references: J Neurosci. 2008 Jan 16;28(3):737-48
references: 18199773
references: Brain Res Mol Brain Res. 1996 Jun;38(2):200-8
references: 8793108
references: Am J Pathol. 1999 Oct;155(4):1163-72
references: 10514399
references: Neurobiol Aging. 2005 Jul;26(7):1015-22
references: 15748781
references: Neurochem Res. 2006 Dec;31(12):1473-80
references: 17120162
references: J Biol Chem. 2004 Aug 13;279(33):34873-81
references: 15190058
references: Biochemistry. 1995 Feb 14;34(6):1988-96
references: 7531497
references: J Neuropathol Exp Neurol. 2008 May;67(5):470-83
references: 18431250
references: FASEB J. 2013 May;27(5):1847-58
references: 23335053
references: Mol Neurodegener. 2008 Jul 10;3:8
references: 18616804
references: Brain. 2005 Nov;128(Pt 11):2645-53
references: 16014652
references: Mol Cell Biochem. 1996 Jan 26;154(2):143-51
references: 8717428
references: Biochemistry. 2007 Mar 27;46(12):3856-61
references: 17338548
references: Biochem Soc Trans. 2010 Aug;38(4):955-61
references: 20658984
references: J Cell Sci. 2010 Jan 1;123(Pt 1):13-22
references: 20016062
references: J Neurosci. 2003 Aug 6;23(18):6972-81
references: 12904458
references: J Biol Chem. 1993 Nov 15;268(32):24374-84
references: 8226987
references: Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7737-41
references: 9636220
references: Biochim Biophys Acta. 2010 Feb;1800(2):96-106
references: 19647786
references: Acta Neuropathol. 2007 Jan;113(1):63-73
references: 17089132
references: J Neurochem. 1995 Aug;65(2):732-8
references: 7616230
references: J Cell Biol. 1991 Nov;115(3):717-30
references: 1918161
references: J Biol Chem. 2006 Sep 1;281(35):25388-97
references: 16818492
references: Brain Res Mol Brain Res. 2004 Jul 26;126(2):146-56
references: 15249138
references: J Biol Chem. 2001 Oct 12;276(41):37967-73
references: 11495914
references: Nat Rev Drug Discov. 2008 Dec;7(12):1013-30
references: 19043451
references: Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8864-9
references: 16735465
references: Eur J Neurosci. 2006 Apr;23(8):2078-86
references: 16630055
references: Biochemistry. 2005 Aug 30;44(34):11466-75
references: 16114883
references: Biochemistry. 2000 Jan 18;39(2):424-31
references: 10631004
references: J Clin Invest. 2004 Jul;114(1):121-30
references: 15232619
references: Curr Alzheimer Res. 2010 Dec;7(8):656-64
references: 20678074
references: Acta Neuropathol. 2009 Jul;118(1):71-86
references: 19238406
references: J Neurochem. 2008 Jun 1;105(6):2098-108
references: 18284615
references: FEBS Lett. 1994 Aug 29;351(1):80-4
references: 8076698
references: J Neurosci. 2007 Mar 21;27(12):3090-7
references: 17376970
references: J Neurochem. 1993 Sep;61(3):921-7
references: 8395566
references: Am J Pathol. 2004 Aug;165(2):523-31
references: 15277226
references: FEBS Lett. 2006 Jun 26;580(15):3582-8
references: 16753151
references: Brain Res. 1977 Feb;121(2):327-42
references: 832166
references: Brain Res. 1989 Jan 16;477(1-2):90-9
references: 2495152
references: Proc Natl Acad Sci U S A. 1986 Jul;83(13):4913-7
references: 3088567
references: Mol Biosyst. 2011 May;7(5):1420-9
references: 21327254
references: Biochem Biophys Res Commun. 2008 Oct 10;375(1):59-62
references: 18671940
references: J Neurosci. 2004 Sep 8;24(36):7895-902
references: 15356202
references: J Alzheimers Dis. 2009;16(3):619-26
references: 19276556
references: Neuron. 1989 Oct;3(4):519-26
references: 2484340
references: Acta Neuropathol. 2007 May;113(5):501-11
references: 17372746
references: EMBO J. 1993 Jan;12(1):365-70
references: 7679073
references: Proc Natl Acad Sci U S A. 1997 Jan 7;94(1):298-303
references: 8990203
references: Biochemistry. 2011 Nov 8;50(44):9446-56
references: 21942206
references: J Biol Chem. 2006 Dec 22;281(51):39413-23
references: 17056594
references: J Biol Chem. 2000 Sep 29;275(39):30335-43
references: 10869348
references: Nature. 1998 Jun 18;393(6686):702-5
references: 9641683
references: Nat Med. 1996 Jul;2(7):783-7
references: 8673924
references: Cell Motil Cytoskeleton. 2006 Nov;63(11):710-24
references: 16960886
references: Am J Pathol. 2008 Jan;172(1):123-31
references: 18079436
references: J Biol Chem. 1996 Nov 15;271(46):28741-4
references: 8910513
references: Mol Cell Biol. 1992 Aug;12(8):3346-55
references: 1630450
references: Brain. 2003 Apr;126(Pt 4):814-26
references: 12615641
references: FEBS Lett. 1995 Jan 16;358(1):4-8
references: 7821426
references: J Neuropathol Exp Neurol. 2000 Nov;59(11):990-1001
references: 11089577
references: J Neuropathol Exp Neurol. 2009 May;68(5):503-14
references: 19525898
references: Am J Pathol. 2005 Jun;166(6):1761-71
references: 15920161
references: Science. 2001 Jul 27;293(5530):711-4
references: 11408621
references: J Biol Chem. 1996 May 10;271(19):11059-62
references: 8626647
references: Mol Cell Proteomics. 2010 Jan;9(1):153-60
references: 19692427
references: Neuron. 2007 Feb 1;53(3):337-51
references: 17270732
references: J Biol Chem. 2004 Dec 24;279(52):54716-23
references: 15494420
references: FEBS Lett. 2011 Sep 2;585(17):2653-9
references: 21806989
references: Biochim Biophys Acta. 2004 Jul 6;1673(1-2):13-28
references: 15238246
references: Am J Pathol. 2005 May;166(5):1499-514
references: 15855649
references: Eur J Neurosci. 2005 Oct;22(8):1942-50
references: 16262633
references: Biol Chem Hoppe Seyler. 1994 Feb;375(2):113-26
references: 8192856
references: Biol Chem. 1998 Nov;379(11):1307-17
references: 9865603
references: Mol Neurodegener. 2009 May 02;4:18
references: 19409104
references: Acta Neuropathol. 2012 Jan;123(1):133-51
references: 22083255
references: Nature. 2010 Apr 22;464(7292):1201-4
references: 20357768
references: Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17319-20
references: 23047690