View source for Tau protein

{{short description|Group of six protein isoforms produced from the MAPT gene}}
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{{Infobox_gene}}

The '''tau proteins''' (abbreviated from '''t'''ubulin '''a'''ssociated '''u'''nit<ref name="pmid1057175"></ref>) form a group of six highly soluble [[protein isoforms]] produced by [[alternative splicing]] from the [[gene]] ''MAPT'' ([[microtubule-associated protein]] tau).<ref name="pmid3131773">{{cite journal | vauthors = Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A | title = Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 85 | issue = 11 | pages = 4051–5 | date = June 1988 | pmid = 3131773 | pmc = 280359 | doi = 10.1073/pnas.85.11.4051 | bibcode = 1988PNAS...85.4051G | doi-access = free }}</ref><ref name="pmid2484340">{{cite journal | vauthors = Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA | title = Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease | journal = Neuron | volume = 3 | issue = 4 | pages = 519–26 | date = October 1989 | pmid = 2484340 | doi = 10.1016/0896-6273(89)90210-9 | s2cid = 19627629 }}</ref> They have roles primarily in maintaining the stability of [[microtubules]] in [[axons]] and are abundant in the [[neuron]]s of the [[central nervous system]] (CNS), where the [[cerebral cortex]] has the highest abundance.<ref>{{cite journal | vauthors = Sjölin K, Kultima K, Larsson A, Freyhult E, Zjukovskaja C, Alkass K, Burman J | title = Distribution of five clinically important neuroglial proteins in the human brain | journal = Molecular Brain | volume = 15 | issue = 1 | pages = 52 | date = June 2022 | pmid = 35765081 | pmc = 9241296 | doi = 10.1186/s13041-022-00935-6 | doi-access = free }}</ref> They are less common elsewhere but are also expressed at very low levels in CNS [[astrocyte]]s and [[oligodendrocyte]]s.<ref name="pmid1903170">{{cite journal | vauthors = Shin RW, Iwaki T, Kitamoto T, Tateishi J | title = Hydrated autoclave pretreatment enhances tau immunoreactivity in formalin-fixed normal and Alzheimer's disease brain tissues | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 64 | issue = 5 | pages = 693–702 | date = May 1991 | pmid = 1903170 }}</ref>

Pathologies and [[dementia]]s of the [[nervous system]] such as [[Alzheimer's disease]] and [[Parkinson's disease]]<ref name="pmid20678581">{{cite journal | vauthors = Lei P, Ayton S, Finkelstein DI, Adlard PA, Masters CL, Bush AI | title = Tau protein: relevance to Parkinson's disease | journal = The International Journal of Biochemistry & Cell Biology | volume = 42 | issue = 11 | pages = 1775–8 | date = November 2010 | pmid = 20678581 | doi = 10.1016/j.biocel.2010.07.016 }}</ref> are associated with tau proteins that have become [[hyperphosphorylated]] insoluble aggregates called [[neurofibrillary tangles]]. The tau proteins were identified in 1975 as heat-stable proteins essential for microtubule assembly,<ref name="pmid1057175">{{cite journal | vauthors = Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW | title = A protein factor essential for microtubule assembly | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 72 | issue = 5 | pages = 1858–62 | date = May 1975 | pmid = 1057175 | pmc = 432646 | doi = 10.1073/pnas.72.5.1858 | bibcode = 1975PNAS...72.1858W | doi-access = free }}</ref><ref name="Cleveland_1977">{{cite journal | vauthors = Cleveland DW, Hwo SY, Kirschner MW | title = Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin | journal = Journal of Molecular Biology | volume = 116 | issue = 2 | pages = 207–25 | date = October 1977 | pmid = 599557 | doi = 10.1016/0022-2836(77)90213-3 }}</ref> and since then they have been characterized as [[intrinsically disordered proteins]].<ref>{{cite journal | vauthors = Cleveland DW, Hwo SY, Kirschner MW | title = Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly | journal = Journal of Molecular Biology | volume = 116 | issue = 2 | pages = 227–47 | date = October 1977 | pmid = 146092 | doi = 10.1016/0022-2836(77)90214-5 }}</ref>

[[File:MAP2-tau in neurons.jpg|333px|thumb|Neurons were grown in tissue culture and stained with antibody to [[MAP2]] protein in green and MAP tau in red using the [[immunofluorescence]] technique. MAP2 is found only in dendrites and perikarya, while tau is found not only in the dendrites and perikarya but also in axons. As a result, axons appear red while the dendrites and perikarya appear yellow, due to superimposition of the red and green signals. DNA is shown in blue using the [[DAPI]] stain which highlights the nuclei. Image courtesy [[EnCor Biotechnology|EnCor Biotechnology Inc]].]]

== Function ==

=== Microtubule stabilization ===
Tau proteins are found more often in neurons than in non-neuronal cells in humans. One of tau's main functions is to modulate the stability of axonal [[microtubule]]s.<ref name="Cleveland_1977" />''<ref name="pmid31488613">{{cite journal | vauthors = Papanikolopoulou K, Roussou IG, Gouzi JY, Samiotaki M, Panayotou G, Turin L, Skoulakis EM | title = Drosophila Tau Negatively Regulates Translation and Olfactory Long-Term Memory, But Facilitates Footshock Habituation and Cytoskeletal Homeostasis | journal = The Journal of Neuroscience | volume = 39 | issue = 42 | pages = 8315–8329 | date = October 2019 | pmid = 31488613 | pmc = 6794924 | doi = 10.1523/JNEUROSCI.0391-19.2019 }}</ref>'' Other nervous system [[microtubule-associated proteins]] (MAPs) may perform similar functions, as suggested by tau [[knockout mice]] that did not show abnormalities in brain development – possibly because of compensation in tau deficiency by other MAPs.<ref name=":1">{{cite journal | vauthors = Harada A, Oguchi K, Okabe S, Kuno J, Terada S, Ohshima T, Sato-Yoshitake R, Takei Y, Noda T, Hirokawa N | title = Altered microtubule organization in small-calibre axons of mice lacking tau protein | journal = Nature | volume = 369 | issue = 6480 | pages = 488–91 | date = June 1994 | pmid = 8202139 | doi = 10.1038/369488a0 | bibcode = 1994Natur.369..488H | s2cid = 4322543 }}</ref><ref name="pmid8202139">{{cite journal | vauthors = Wang JZ, Liu F | title = Microtubule-associated protein tau in development, degeneration and protection of neurons | journal = Progress in Neurobiology | volume = 85 | issue = 2 | pages = 148–75 | date = June 2008 | pmid = 18448228 | doi = 10.1016/j.pneurobio.2008.03.002 | s2cid = 32708424 }}</ref><ref>{{cite journal | vauthors = Ke YD, Suchowerska AK, van der Hoven J, De Silva DM, Wu CW, van Eersel J, Ittner A, Ittner LM | title = Lessons from tau-deficient mice | journal = International Journal of Alzheimer's Disease | volume = 2012 | issue = 873270 | pages = 873270 | date = June 2012 | pmid = 22720190 | pmc = 3375147 | doi = 10.1155/2012/873270 | doi-access = free }}</ref>

Although tau is present in [[dendrites]] at low levels, where it is involved in postsynaptic scaffolding,<ref>{{cite journal | vauthors = Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Götz J | title = Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models | journal = Cell | volume = 142 | issue = 3 | pages = 387–97 | date = August 2010 | pmid = 20655099 | doi = 10.1016/j.cell.2010.06.036 | s2cid = 18776289 | doi-access = free }}</ref> it is active primarily in the [[Anatomical terms of location#Proximal and distal|distal]] portions of [[axons]], where it provides microtubule stabilization but also flexibility as needed. Tau proteins interact with [[tubulin]] to stabilize microtubules and promote tubulin assembly into microtubules.<ref name="Cleveland_1977" /> Tau has two ways of controlling microtubule stability: [[protein isoform|isoforms]] and [[phosphorylation]].

In addition to its microtubule-stabilizing function, Tau has also been found to recruit [[Signal transduction|signaling proteins]] and to regulate [[Axonal transport|microtubule-mediated axonal transport]].<ref>{{cite journal | vauthors = Dehmelt L, Halpain S | title = The MAP2/Tau family of microtubule-associated proteins | journal = Genome Biology | volume = 6 | issue = 1 | pages = 204 | date = 2004 | pmid = 15642108 | pmc = 549057 | doi = 10.1186/gb-2004-6-1-204 | doi-access = free }}</ref>

=== mRNA translation ===
Tau is a negative regulator of mRNA [[Translation (biology)|translation]] in ''[[Drosophila]]'',<ref name="pmid31488613" /> mouse,<ref>{{Cite journal|vauthors=Evans HT, Benetatos J, van Roigen M, Bodea LG, Götz J|date=2019-07-01|title=Decreased synthesis of ribosomal proteins in tauopathy revealed by non-canonical amino acid labelling|journal=The EMBO Journal|volume=38|issue=13|pages=e101174|doi=10.15252/embj.2018101174|issn=0261-4189|pmc=6600635|pmid=31268600}}</ref> and human<ref name=":2">{{cite journal | vauthors = Meier S, Bell M, Lyons DN, Rodriguez-Rivera J, Ingram A, Fontaine SN, Mechas E, Chen J, Wolozin B, LeVine H, Zhu H, Abisambra JF | title = Pathological Tau Promotes Neuronal Damage by Impairing Ribosomal Function and Decreasing Protein Synthesis | journal = The Journal of Neuroscience | volume = 36 | issue = 3 | pages = 1001–7 | date = January 2016 | pmid = 26791227 | pmc = 4719006 | doi = 10.1523/JNEUROSCI.3029-15.2016 }}</ref> brains, through its binding to [[ribosome]]s, which results in impaired ribosomal function,<ref>{{Cite journal|first5=Jürgen|vauthors=Evans HT, Taylor D, Kneynsberg A, Bodea LG, Götz J|date=2021-06-19|title=Altered ribosomal function and protein synthesis caused by tau|journal=Acta Neuropathologica Communications|volume=9|issue=1|pages=110|doi=10.1186/s40478-021-01208-4|issn=2051-5960|pmc=8214309|pmid=34147135 |doi-access=free }}</ref> reduction of [[Protein biosynthesis|protein synthesis]] and altered synaptic function.''<ref name="pmid31488613" />''<ref name=":2" /> Tau interacts specifically with several [[ribosomal protein]]s, including the crucial regulator of translation [[Ribosomal protein s6|rpS6]].<ref>{{cite journal | vauthors = Koren SA, Hamm MJ, Meier SE, Weiss BE, Nation GK, Chishti EA, Arango JP, Chen J, Zhu H, Blalock EM, Abisambra JF | title = Tau drives translational selectivity by interacting with ribosomal proteins | journal = Acta Neuropathologica | volume = 137 | issue = 4 | pages = 571–583 | date = April 2019 | pmid = 30759285 | pmc = 6426815 | doi = 10.1007/s00401-019-01970-9 }}</ref>

=== Behavior ===
The primary non-cellular functions of tau is to negatively regulate [[long-term memory]]<ref name="pmid31488613" /> and to facilitate [[habituation]] (a form of non-associative learning),<ref name="pmid31488613" /> two higher and more integrated physiological functions. Since regulation of tau is critical for memory, this could explain the linkage between tauopathies and cognitive impairment.

In mice, while the reported tau knockout strains present without overt phenotype when young,<ref name=":1" /><ref>{{cite journal | vauthors = Dawson HN, Ferreira A, Eyster MV, Ghoshal N, Binder LI, Vitek MP | title = Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice | journal = Journal of Cell Science | volume = 114 | issue = Pt 6 | pages = 1179–87 | date = March 2001 | doi = 10.1242/jcs.114.6.1179 | pmid = 11228161 | url = https://jcs.biologists.org/content/114/6/1179 }}</ref><ref>{{cite journal | vauthors = Fujio K, Sato M, Uemura T, Sato T, Sato-Harada R, Harada A | title = 14-3-3 proteins and protein phosphatases are not reduced in tau-deficient mice | journal = NeuroReport | volume = 18 | issue = 10 | pages = 1049–52 | date = July 2007 | pmid = 17558294 | doi = 10.1097/WNR.0b013e32818b2a0b | s2cid = 25235996 | url = https://insights.ovid.com/crossref?an=00001756-200707020-00020 }}</ref> when aged, they show some muscle weakness, hyperactivity, and impaired [[fear conditioning]].<ref name=":3">{{cite journal | vauthors = Ikegami S, Harada A, Hirokawa N | title = Muscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice | journal = Neuroscience Letters | volume = 279 | issue = 3 | pages = 129–32 | date = February 2000 | pmid = 10688046 | doi = 10.1016/s0304-3940(99)00964-7 | s2cid = 31204860 }}</ref> However, neither spatial learning in mice,<ref name=":3" /><ref>{{cite journal | vauthors = Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L | title = Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model | journal = Science | volume = 316 | issue = 5825 | pages = 750–4 | date = May 2007 | pmid = 17478722 | doi = 10.1126/science.1141736 | bibcode = 2007Sci...316..750R | s2cid = 32771613 }}</ref><ref>{{cite journal | vauthors = Dawson HN, Cantillana V, Jansen M, Wang H, Vitek MP, Wilcock DM, Lynch JR, Laskowitz DT | title = Loss of tau elicits axonal degeneration in a mouse model of Alzheimer's disease | journal = Neuroscience | volume = 169 | issue = 1 | pages = 516–31 | date = August 2010 | pmid = 20434528 | pmc = 2900546 | doi = 10.1016/j.neuroscience.2010.04.037 }}</ref> nor short-term memory (learning) in ''Drosophila''<ref name="pmid31488613" /> seems to be affected by the absence of tau.

In addition, tau knockout mice have abnormal [[Circadian rhythm|sleep-wake cycle]], with increased wakefulness periods and decreased [[Non-rapid eye movement sleep|non-rapid eye movements (NREM) sleep]] time.<ref>{{cite journal | vauthors = Cantero JL, Hita-Yañez E, Moreno-Lopez B, Portillo F, Rubio A, Avila J | title = Tau protein role in sleep-wake cycle | journal = Journal of Alzheimer's Disease | volume = 21 | issue = 2 | pages = 411–21 | date = August 2010 | pmid = 20555133 | doi = 10.3233/JAD-2010-100285 | url = https://content.iospress.com/articles/journal-of-alzheimers-disease/jad100285 }}</ref>

=== Other functions ===
Other typical functions of tau include [[Cell signaling|cellular signalling]], [[Neurodevelopment|neuronal development]], [[neuroprotection]] and [[apoptosis]].<ref name="pmid8202139"/> Atypical, non-standard roles of tau<ref>{{cite journal | vauthors = Sotiropoulos I, Galas MC, Silva JM, Skoulakis E, Wegmann S, Maina MB, Blum D, Sayas CL, Mandelkow EM, Mandelkow E, Spillantini MG, Sousa N, Avila J, Medina M, Mudher A, Buee L | title = Atypical, non-standard functions of the microtubule associated Tau protein | journal = Acta Neuropathologica Communications | volume = 5 | issue = 1 | pages = 91 | date = November 2017 | pmid = 29187252 | pmc = 5707803 | doi = 10.1186/s40478-017-0489-6 | doi-access = free }}</ref> are also under current investigation, such as its involvement in [[chromosome]] stability, its interaction with the cellular [[transcriptome]], its interaction with other cytoskeletal or synaptic proteins, its involvement in [[myelination]] or in brain [[insulin]] signaling, its role in the exposure to [[chronic stress]] and in [[Depression (mood)|depression]], etc.

== Genetics ==

In humans, the ''MAPT'' gene for encoding tau protein is located on [[Chromosome 17 (human)|chromosome 17]]q21, containing 16 [[exon]]s.<ref>{{cite journal | vauthors = Neve RL, Harris P, Kosik KS, Kurnit DM, Donlon TA | title = Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2 | journal = Brain Research | volume = 387 | issue = 3 | pages = 271–80 | date = December 1986 | pmid = 3103857 | doi = 10.1016/0169-328x(86)90033-1 }}</ref> The major tau protein in the human brain is [[Transcription (genetics)|encoded]] by 11 exons. Exons 2, 3 and 10 are [[alternative splicing|alternatively spliced]], which leads to the formation of six tau isoforms.<ref>{{cite journal | vauthors = Sergeant N, Delacourte A, Buée L | title = Tau protein as a differential biomarker of tauopathies | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1739 | issue = 2–3 | pages = 179–97 | date = January 2005 | pmid = 15615637 | doi = 10.1016/j.bbadis.2004.06.020 | doi-access = free }}</ref> In the human brain, tau proteins constitute a family of six [[Protein isoform|isoforms]] with a range of 352–441 amino acids. Tau isoforms are different in having either zero, one, or two inserts of 29 amino acids at the [[N-terminus|N-terminal part]] (exons 2 and 3) and three or four repeat-regions at the [[C-terminal]] part (exon 10). Thus, the longest isoform in the [[Central nervous system|CNS]] has four repeats (R1, R2, R3 and R4) and two inserts (441 amino acids total), while the shortest isoform has three repeats (R1, R3 and R4) and no insert (352 amino acids total).

The ''MAPT'' gene has two [[haplogroup]]s, H1 and H2, in which the gene appears in inverted orientations. Haplogroup H2 is common only in Europe and in people with European ancestry. Haplogroup H1 appears to be associated with increased probability of certain dementias, such as Alzheimer's disease. The presence of both haplogroups in Europe means that recombination between inverted haplotypes can result in the lack of one of the functioning copies of the gene, resulting in congenital defects.<ref name="pmid16906163">{{cite journal | vauthors = Shaw-Smith C, Pittman AM, Willatt L, Martin H, Rickman L, Gribble S, Curley R, Cumming S, Dunn C, Kalaitzopoulos D, Porter K, Prigmore E, Krepischi-Santos AC, Varela MC, Koiffmann CP, Lees AJ, Rosenberg C, Firth HV, de Silva R, Carter NP | title = Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability | journal = Nature Genetics | volume = 38 | issue = 9 | pages = 1032–7 | date = September 2006 | pmid = 16906163 | doi = 10.1038/ng1858 | s2cid = 38047848 }}</ref><ref name="pmid19165922">{{cite journal | vauthors = Zody MC, Jiang Z, Fung HC, Antonacci F, Hillier LW, Cardone MF, Graves TA, Kidd JM, Cheng Z, Abouelleil A, Chen L, Wallis J, Glasscock J, Wilson RK, Reily AD, Duckworth J, Ventura M, Hardy J, Warren WC, Eichler EE | title = Evolutionary toggling of the MAPT 17q21.31 inversion region | journal = Nature Genetics | volume = 40 | issue = 9 | pages = 1076–83 | date = September 2008 | pmid = 19165922 | pmc = 2684794 | doi = 10.1038/ng.193 }}</ref><ref name="pmid18648385">{{cite journal | vauthors = Almos PZ, Horváth S, Czibula A, Raskó I, Sipos B, Bihari P, Béres J, Juhász A, Janka Z, Kálmán J | title = H1 tau haplotype-related genomic variation at 17q21.3 as an Asian heritage of the European Gypsy population | journal = Heredity | volume = 101 | issue = 5 | pages = 416–9 | date = November 2008 | pmid = 18648385 | doi = 10.1038/hdy.2008.70 | doi-access = free }}</ref><ref name="pmid16042549">{{cite journal | vauthors = Hardy J, Pittman A, Myers A, Gwinn-Hardy K, Fung HC, de Silva R, Hutton M, Duckworth J | title = Evidence suggesting that Homo neanderthalensis contributed the H2 MAPT haplotype to Homo sapiens | journal = Biochemical Society Transactions | volume = 33 | issue = Pt 4 | pages = 582–5 | date = August 2005 | pmid = 16042549 | doi = 10.1042/BST0330582 }}</ref>

== Structure ==

Six tau isoforms exist in human brain tissue, and they are distinguished by their number of binding [[protein domain|domains]]. Three isoforms have three binding domains and the other three have four binding domains. The binding domains are located in the [[C-terminal end|carboxy-terminus]] of the protein and are positively charged (allowing it to bind to the negatively charged microtubule). The isoforms with four binding domains are better at stabilizing microtubules than those with three binding domains. Tau is a [[phosphoprotein]] with 79 potential [[serine]] (Ser) and [[threonine]] (Thr) phosphorylation sites on the longest tau isoform. Phosphorylation has been reported on approximately 30 of these sites in normal tau proteins.<ref name="pmid9169588">{{cite journal | vauthors = Billingsley ML, Kincaid RL | title = Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration | journal = The Biochemical Journal | volume = 323 | issue = 3 | pages = 577–91 | date = May 1997 | pmid = 9169588 | pmc = 1218358 | doi = 10.1042/bj3230577 }}</ref>

Phosphorylation of tau is regulated by a host of [[kinase]]s, including [[Protein kinase N1|PKN]], a [[Protein kinase#Serine.2Fthreonine-specific protein kinases|serine/threonine kinase]]. When PKN is activated, it phosphorylates tau, resulting in disruption of microtubule organization.<ref name="pmid11104762">{{cite journal | vauthors = Taniguchi T, Kawamata T, Mukai H, Hasegawa H, Isagawa T, Yasuda M, Hashimoto T, Terashima A, Nakai M, Mori H, Ono Y, Tanaka C | title = Phosphorylation of tau is regulated by PKN | journal = The Journal of Biological Chemistry | volume = 276 | issue = 13 | pages = 10025–31 | date = March 2001 | pmid = 11104762 | doi = 10.1074/jbc.M007427200 | doi-access = free }}</ref> Phosphorylation of tau is also developmentally regulated. For example, fetal tau is more highly phosphorylated in the embryonic CNS than adult tau.<ref name="pmid1560225">{{cite journal | vauthors = Kanemaru K, Takio K, Miura R, Titani K, Ihara Y | title = Fetal-type phosphorylation of the tau in paired helical filaments | journal = Journal of Neurochemistry | volume = 58 | issue = 5 | pages = 1667–75 | date = May 1992 | pmid = 1560225 | doi = 10.1111/j.1471-4159.1992.tb10039.x | s2cid = 94265621 }}</ref> The degree of phosphorylation in all six isoforms decreases with age due to the activation of [[phosphatase]]s.<ref name="pmid7983034">{{cite journal | vauthors = Mawal-Dewan M, Henley J, Van de Voorde A, Trojanowski JQ, Lee VM | title = The phosphorylation state of tau in the developing rat brain is regulated by phosphoprotein phosphatases | journal = The Journal of Biological Chemistry | volume = 269 | issue = 49 | pages = 30981–7 | date = December 1994 | doi = 10.1016/S0021-9258(18)47378-4 | pmid = 7983034 | doi-access = free }}</ref> Like kinases, phosphatases too play a role in regulating the phosphorylation of tau. For example, [[PP2A]] and [[PP2B]] are both present in human brain tissue and have the ability to [[dephosphorylate]] Ser396.<ref name="pmid7946342">{{cite journal | vauthors = Matsuo ES, Shin RW, Billingsley ML, Van deVoorde A, O'Connor M, Trojanowski JQ, Lee VM | title = Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer's disease paired helical filament tau | journal = Neuron | volume = 13 | issue = 4 | pages = 989–1002 | date = October 1994 | pmid = 7946342 | doi = 10.1016/0896-6273(94)90264-X | s2cid = 40592137 }}</ref> The binding of these phosphatases to tau affects tau's association with microtubules.

Phosphorylation of tau has also been suggested to be regulated by [[O-GlcNAc|''O''-GlcNAc]] modification at various Ser and Thr residues.<ref>{{cite journal | vauthors = Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong CX | title = O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 29 | pages = 10804–10809 | date = July 2004 | pmid = 15249677 | pmc = 490015 | doi = 10.1073/pnas.0400348101 | doi-access = free | bibcode = 2004PNAS..10110804L }}</ref>

== Mechanism ==
The accumulation of hyperphosphorylated tau in neurons is associated with neurofibrillary degeneration.<ref>{{cite journal | vauthors = Alonso AD, Grundke-Iqbal I, Barra HS, Iqbal K | title = Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 1 | pages = 298–303 | date = January 1997 | pmid = 8990203 | pmc = 19321 | doi = 10.1073/pnas.94.1.298 | bibcode = 1997PNAS...94..298A | doi-access = free }}</ref> The actual mechanism of how tau propagates from one cell to another is not well identified. Also, other mechanisms, including tau release and toxicity, are unclear. As tau aggregates, it replaces tubulin, which in turn enhances fibrilization of tau.<ref>{{cite journal | vauthors = Frost B, Jacks RL, Diamond MI | title = Propagation of tau misfolding from the outside to the inside of a cell | journal = The Journal of Biological Chemistry | volume = 284 | issue = 19 | pages = 12845–52 | date = May 2009 | pmid = 19282288 | pmc = 2676015 | doi = 10.1074/jbc.M808759200 | doi-access = free }}</ref> Several propagation methods have been proposed that occur by synaptic contact such as synaptic cell adhesion proteins, neuronal activity and other synaptic and non-synaptic mechanisms.<ref>{{cite journal | vauthors = Calafate S, Buist A, Miskiewicz K, Vijayan V, Daneels G, de Strooper B, de Wit J, Verstreken P, Moechars D | title = Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation | journal = Cell Reports | volume = 11 | issue = 8 | pages = 1176–83 | date = May 2015 | pmid = 25981034 | doi = 10.1016/j.celrep.2015.04.043 | url = https://lirias.kuleuven.be/bitstream/123456789/499409/5/Synaptic%2BContacts%2BEnhance%2BCell-to-Cell%2BTau%2BPathology%2BPropagation.pdf | doi-access = free }}</ref> The mechanism of tau aggregation is still not completely elucidated, but several factors favor this process, including tau phosphorylation and zinc ions.<ref>{{cite journal | vauthors = Roman AY, Devred F, Byrne D, La Rocca R, Ninkina NN, Peyrot V, Tsvetkov PO | title = Zinc Induces Temperature-Dependent Reversible Self-Assembly of Tau | journal = Journal of Molecular Biology | volume = 431 | issue = 4 | pages = 687–695 | date = February 2019 | pmid = 30580037 | doi = 10.1016/j.jmb.2018.12.008 | url = https://hal-amu.archives-ouvertes.fr/hal-01981683 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Fichou Y, Al-Hilaly YK, Devred F, Smet-Nocca C, Tsvetkov PO, Verelst J, Winderickx J, Geukens N, Vanmechelen E, Perrotin A, Serpell L, Hanseeuw BJ, Medina M, Buée L, Landrieu I | title = The elusive tau molecular structures: can we translate the recent breakthroughs into new targets for intervention? | journal = Acta Neuropathologica Communications | volume = 7 | issue = 1 | pages = 31 | date = March 2019 | pmid = 30823892 | pmc = 6397507 | doi = 10.1186/s40478-019-0682-x | doi-access = free }}</ref>

=== Release ===
Tau is involved in uptake and release processes, which are known as seeding. Uptake of tau protein requires the presence of [[heparan sulfate proteoglycans]] at the cell surface, which happens by [[macropinocytosis]].<ref>{{cite journal | vauthors = Goedert M, Eisenberg DS, Crowther RA | title = Propagation of Tau Aggregates and Neurodegeneration | journal = Annual Review of Neuroscience | volume = 40 | issue = 1 | pages = 189–210 | date = July 2017 | pmid = 28772101 | doi = 10.1146/annurev-neuro-072116-031153 | doi-access = free }}</ref> On the other hand, tau release depends on neuronal activity. Many factors influence tau release such as, for example, the isoforms or ''MAPT'' mutations that change the extracellular level of tau.<ref>{{cite journal | vauthors = Yamada K | title = Extracellular Tau and Its Potential Role in the Propagation of Tau Pathology | language = en | journal = Frontiers in Neuroscience | volume = 11 | pages = 667 | date = 2017 | pmid = 29238289 | pmc = 5712583 | doi = 10.3389/fnins.2017.00667 | doi-access = free }}</ref> According to Asai and his colleagues, the spreading of tau protein occurs from the [[entorhinal cortex]] to the [[hippocampal]] region in the early stages of the disease. They also suggested that [[microglia]] were also involved in the transport process, and their actual role is still unknown.<ref>{{cite journal | vauthors = Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kügler S, Ikezu T | title = Depletion of microglia and inhibition of exosome synthesis halt tau propagation | journal = Nature Neuroscience | volume = 18 | issue = 11 | pages = 1584–93 | date = November 2015 | pmid = 26436904 | pmc = 4694577 | doi = 10.1038/nn.4132 }}</ref>

=== Toxicity ===
Tau causes toxic effects through its accumulation inside cells. Many enzymes are involved in toxicity mechanism such as [[KIN2/PAR-1/MARK kinase family|PAR-1]] kinase. This enzyme stimulates phosphorylation of serine 262 and 356, which in turn leads to activate other kinases ([[GSK-3]] and [[CDK5]]) that cause disease-associated [[phosphoepitopes]].<ref>{{cite journal | vauthors = Nishimura I, Yang Y, Lu B | title = PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila | journal = Cell | volume = 116 | issue = 5 | pages = 671–82 | date = March 2004 | pmid = 15006350 | doi = 10.1016/S0092-8674(04)00170-9 | s2cid = 18896805 | doi-access = free }}</ref> The degree of toxicity is affected by different factors, such as the degree of microtubule binding.<ref>{{cite journal | vauthors = Chatterjee S, Sang TK, Lawless GM, Jackson GR | title = Dissociation of tau toxicity and phosphorylation: role of GSK-3beta, MARK and Cdk5 in a Drosophila model | journal = Human Molecular Genetics | volume = 18 | issue = 1 | pages = 164–77 | date = January 2009 | pmid = 18930955 | pmc = 2644648 | doi = 10.1093/hmg/ddn326 }}</ref><ref>{{cite journal | vauthors = Lee HG, Perry G, Moreira PI, Garrett MR, Liu Q, Zhu X, Takeda A, Nunomura A, Smith MA | title = Tau phosphorylation in Alzheimer's disease: pathogen or protector? | journal = Trends in Molecular Medicine | volume = 11 | issue = 4 | pages = 164–9 | date = April 2005 | pmid = 15823754 | doi = 10.1016/j.molmed.2005.02.008 | hdl = 10316/4769 | hdl-access = free }}</ref> Toxicity could also happen by [[neurofibrillary tangle]]s (NFTs), which leads to cell death and cognitive decline.

== Clinical significance ==
{{Further|Tauopathy}}
[[Hyperphosphorylation]] of the tau protein (tau [[Inclusion bodies|inclusions]], pTau) can result in the [[self-assembly]] of [[neurofibrillary tangle|tangles]] of paired helical filaments and straight filaments, which are involved in the [[pathogenesis]] of [[Alzheimer's disease]], [[frontotemporal dementia]] and other [[tauopathy|tauopathies]].<ref name="pmid11381127">{{cite journal | vauthors = Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K | title = Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 12 | pages = 6923–8 | date = June 2001 | pmid = 11381127 | pmc = 34454 | doi = 10.1073/pnas.121119298 | bibcode = 2001PNAS...98.6923A | doi-access = free }}</ref> All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments in the Alzheimer's disease brain. In other [[neurodegenerative diseases]], the deposition of aggregates enriched in certain tau isoforms has been reported. When [[protein folding|misfolded]], this otherwise very soluble protein can form extremely insoluble aggregates that contribute to a number of neurodegenerative diseases. Tau protein has a direct effect on the breakdown of a living cell caused by tangles that form and block nerve [[synapses]].<ref name=":0">"Alzheimer's Brain Tangles." Alzheimer's Association, www.alz.org/braintour/tangles.asp.</ref><!-- Unsourced image removed: [[File:tau1.jpg|frame|Microtubules saturated with tau proteins.  Frequent cross bridges are present between microtubules (shown by arrows) (Hirokawa ''et al.'', 1988)]] -->

Gender-specific tau gene expression across different regions of the human brain has recently been implicated in gender differences in the manifestations and risk for tauopathies.<ref name="pmid 27878758">{{cite journal | vauthors = Köglsberger S, Cordero-Maldonado ML, Antony P, Forster JI, Garcia P, Buttini M, Crawford A, Glaab E | title = Gender-Specific Expression of Ubiquitin-Specific Peptidase 9 Modulates Tau Expression and Phosphorylation: Possible Implications for Tauopathies | journal = Molecular Neurobiology | volume = 54 | issue = 10 | pages = 7979–7993 | date = December 2017 | pmid = 27878758 | pmc = 5684262 | doi = 10.1007/s12035-016-0299-z }}</ref> Some aspects of how the disease functions also suggest that it has some similarities to [[prion]] proteins.<ref name="pmid22561167">{{cite journal | vauthors = Hall GF, Patuto BA | title = Is tau ready for admission to the prion club? | journal = Prion | volume = 6 | issue = 3 | pages = 223–33 | date = July 2012 | pmid = 22561167 | pmc = 3399531 | doi = 10.4161/pri.19912 }}</ref>

=== Tau hypothesis of Alzheimer's disease ===

The [[tau hypothesis]] states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into paired-helical-filament (PHF) tau and [[neurofibrillary tangle]]s (NFTs).<ref>{{cite journal | vauthors = Mohandas E, Rajmohan V, Raghunath B | title = Neurobiology of Alzheimer's disease | journal = Indian Journal of Psychiatry | volume = 51 | issue = 1 | pages = 55–61 | date = January 2009 | pmid = 19742193 | pmc = 2738403 | doi = 10.4103/0019-5545.44908 | doi-access = free }}</ref> The stage of the disease determines NFTs' phosphorylation. In AD, at least 19 amino acids are phosphorylated; pre-NFT phosphorylation occurs at serine 199, 202 and 409, while intra-NFT phosphorylation happens at serine 396 and threonine 231.<ref>{{cite journal | vauthors = Augustinack JC, Schneider A, Mandelkow EM, Hyman BT | title = Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease | journal = Acta Neuropathologica | volume = 103 | issue = 1 | pages = 26–35 | date = January 2002 | pmid = 11837744 | doi = 10.1007/s004010100423 | s2cid = 6799990 }}</ref> Through its isoforms and phosphorylation, tau protein interacts with tubulin to stabilize microtubule assembly. All of the six tau isoforms are present in an often hyperphosphorylated state in [[tauopathy|paired helical filaments]] (PHFs) in the AD brain.

Tau mutations have many consequences, including microtubule dysfunction and alteration of the expression level of tau isoforms.<ref>{{cite journal | vauthors = van Slegtenhorst M, Lewis J, Hutton M | title = The molecular genetics of the tauopathies | journal = Experimental Gerontology | volume = 35 | issue = 4 | pages = 461–71 | date = July 2000 | pmid = 10959034 | doi = 10.1016/S0531-5565(00)00114-5 | s2cid = 38730940 }}</ref> Mutations that alter function and isoform expression of tau lead to hyperphosphorylation. The process of tau aggregation in the absence of mutations is not known but might result from increased phosphorylation, [[protease]] action or exposure to [[polyanions]], such as [[glycosaminoglycans]]. Hyperphosphorylated tau disassembles microtubules and sequesters normal tau, MAPT 1 (microtubule associated protein tau 1), MAPT 2 and [[ubiquitin]] into tangles of PHFs. This insoluble structure damages [[cytoplasmic]] functions and interferes with [[axonal transport]], which can lead to cell death.<ref>{{cite journal | vauthors = Mudher A, Lovestone S | title = Alzheimer's disease-do tauists and baptists finally shake hands? | journal = Trends in Neurosciences | volume = 25 | issue = 1 | pages = 22–6 | date = January 2002 | pmid = 11801334 | doi = 10.1016/s0166-2236(00)02031-2 | s2cid = 37380445 }}</ref><ref name=":0" />

Hyperphosphorylated forms of tau protein are the main component of PHFs of NFTs in the brain of AD patients. It has been well demonstrated that regions of tau six-residue segments, namely PHF6 (VQIVYK) and PHF6* (VQIINK), can form tau PHF aggregation in AD. Apart from the PHF6, some other residue sites like Ser285, Ser289, Ser293, Ser305 and Tyr310, located near the C-terminal of the PHF6 sequences, play key roles in the phosphorylation of tau.<ref>{{cite journal | vauthors = Pradeepkiran JA, Reddy PH | title = Structure Based Design and Molecular Docking Studies for Phosphorylated Tau Inhibitors in Alzheimer's Disease | journal = Cells | volume = 8 | issue = 3 | pages = 260 | date = March 2019 | pmid = 30893872 | pmc = 6468864 | doi = 10.3390/cells8030260 | doi-access = free }}</ref> Hyperphosphorylated tau differs in its sensitivity and its [[kinase]] as well as [[alkaline phosphatase]] activity<ref name="pmid25339173">{{cite journal | vauthors = Tepper K, Biernat J, Kumar S, Wegmann S, Timm T, Hübschmann S, Redecke L, Mandelkow EM, Müller DJ, Mandelkow E | title = Oligomer formation of tau protein hyperphosphorylated in cells | journal = The Journal of Biological Chemistry | volume = 289 | issue = 49 | pages = 34389–407 | date = December 2014 | pmid = 25339173 | pmc = 4256367 | doi = 10.1074/jbc.M114.611368 | doi-access = free }}</ref> and is, along with [[beta-amyloid]], a component of the pathologic lesion seen in Alzheimer disease.<ref>{{cite journal | vauthors = Shin RW, Bramblett GT, Lee VM, Trojanowski JQ | title = Alzheimer disease A68 proteins injected into rat brain induce codeposits of beta-amyloid, ubiquitin, and alpha 1-antichymotrypsin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 14 | pages = 6825–8 | date = July 1993 | pmid = 8393578 | pmc = 47025 | doi = 10.1073/pnas.90.14.6825 | bibcode = 1993PNAS...90.6825S | doi-access = free }}</ref><ref>{{cite journal | vauthors = Vincent IJ, Davies P | title = Phosphorylation characteristics of the A68 protein in Alzheimer's disease | journal = Brain Research | volume = 531 | issue = 1–2 | pages = 127–35 | date = October 1990 | pmid = 2126970 | doi = 10.1016/0006-8993(90)90765-4 | s2cid = 23900723 }}</ref> A recent hypothesis identifies the decrease of reelin signaling as the primary change in Alzheimer's disease that leads to the hyperphosphorylation of tau via a decrease in GSK3β inhibition.<ref>{{cite journal | vauthors = Kovács KA | title = Relevance of a Novel Circuit-Level Model of Episodic Memories to Alzheimer's Disease | journal = International Journal of Molecular Sciences | volume = 23 | issue = 1 | pages = 462 | date = December 2021 | doi = 10.3390/ijms23010462 | pmid = 35008886 | pmc = 8745479 | doi-access = free }}</ref>

A68 is a name sometimes given (mostly in older publications) to the [[Hyperphosphorylation|hyperphosphorylated]] form of tau protein found in the brains of individuals with Alzheimer's disease.<ref>{{Citation|title=A68|url=https://medical-dictionary.thefreedictionary.com/A68|work=The Free Dictionary|access-date=2020-01-27}}</ref>

In 2020, researchers from two groups published studies indicating that an [[immunoassay]] blood test for the p-tau-217 form of the protein could diagnose Alzheimer's up to decades before dementia symptoms were evident.<ref>{{Cite news|last=Belluck|first=Pam|date=2020-07-28|title='Amazing, Isn't It?' Long-Sought Blood Test for Alzheimer's in Reach|language=en-US|work=The New York Times|url=https://www.nytimes.com/2020/07/28/health/alzheimers-blood-test.html|access-date=2020-07-29|issn=0362-4331}}</ref><ref>{{cite journal | vauthors = Barthélemy NR, Horie K, Sato C, Bateman RJ | title = Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer's disease | journal = The Journal of Experimental Medicine | volume = 217 | issue = 11 | date = November 2020 | pmid = 32725127 | pmc = 7596823 | doi = 10.1084/jem.20200861 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Palmqvist S, Janelidze S, Quiroz YT, Zetterberg H, Lopera F, Stomrud E, Su Y, Chen Y, Serrano GE, Leuzy A, Mattsson-Carlgren N, Strandberg O, Smith R, Villegas A, Sepulveda-Falla D, Chai X, Proctor NK, Beach TG, Blennow K, Dage JL, Reiman EM, Hansson O | title = Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders | journal = JAMA | volume = 324 | issue = 8 | pages = 772–781 | date = August 2020 | pmid = 32722745 | pmc = 7388060 | doi = 10.1001/jama.2020.12134 }}</ref>

=== Traumatic brain injury ===

Repetitive mild [[traumatic brain injury]] (TBI) is a central component of [[contact sports]], especially [[American football]],<ref>{{cite web|title=Brain Trauma|url=https://www.pbs.org/wgbh/nova/body/brain-trauma.html|website=NOVA|publisher=PBS Online by WGBH}}</ref><ref>{{cite journal | vauthors = Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH | title = Chronic traumatic encephalopathy in a National Football League player | journal = Neurosurgery | volume = 57 | issue = 1 | pages = 128–34; discussion 128–34 | date = July 2005 | pmid = 15987548 | doi = 10.1227/01.NEU.0000163407.92769.ED | s2cid = 196391183 }}</ref> and the concussive force of military blasts.<ref>{{cite journal | vauthors = Goldstein LE, Fisher AM, Tagge CA, Zhang XL, Velisek L, Sullivan JA, Upreti C, Kracht JM, Ericsson M, Wojnarowicz MW, Goletiani CJ, Maglakelidze GM, Casey N, Moncaster JA, Minaeva O, Moir RD, Nowinski CJ, Stern RA, Cantu RC, Geiling J, Blusztajn JK, Wolozin BL, Ikezu T, Stein TD, Budson AE, Kowall NW, Chargin D, Sharon A, Saman S, Hall GF, Moss WC, Cleveland RO, Tanzi RE, Stanton PK, McKee AC | title = Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model | journal = Science Translational Medicine | volume = 4 | issue = 134 | pages = 134ra60 | date = May 2012 | pmid = 22593173 | pmc = 3739428 | doi = 10.1126/scitranslmed.3003716 }}</ref> It can lead to [[chronic traumatic encephalopathy]] (CTE), a condition characterized by fibrillar tangles of hyperphosphorylated tau.<ref>{{cite journal | vauthors = McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH, Lee HS, Wojtowicz SM, Hall G, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC | title = The spectrum of disease in chronic traumatic encephalopathy | journal = Brain | volume = 136 | issue = Pt 1 | pages = 43–64 | date = January 2013 | pmid = 23208308 | pmc = 3624697 | doi = 10.1093/brain/aws307 }}</ref> After severe traumatic brain injury, high levels of tau protein in extracellular fluid in the brain are linked to poor outcomes.<ref name="pmid22116192">{{cite journal | vauthors = Magnoni S, Esparza TJ, Conte V, Carbonara M, Carrabba G, Holtzman DM, Zipfel GJ, Stocchetti N, Brody DL | title = Tau elevations in the brain extracellular space correlate with reduced amyloid-β levels and predict adverse clinical outcomes after severe traumatic brain injury | journal = Brain | volume = 135 | issue = Pt 4 | pages = 1268–80 | date = April 2012 | pmid = 22116192 | pmc = 3326246 | doi = 10.1093/brain/awr286}}
*{{cite web | vauthors = Strait JS |date=December 13, 2011 |title=High levels of tau protein linked to poor recovery after brain injury |website=Washington University in St. Louis |url=http://news.wustl.edu/news/Pages/23103.aspx}}</ref>

=== Prion-like propagation hypothesis ===
The term "prion-like" is often used to describe several aspects of tau pathology in various [[tauopathies]], like [[Alzheimer's disease]] and [[frontotemporal dementia]].<ref>{{cite book | vauthors = Dujardin S, Hyman BT | chapter = Tau Prion-Like Propagation: State of the Art and Current Challenges | title = Tau Biology | journal = Advances in Experimental Medicine and Biology | volume = 1184 | pages = 305–325 | date = 2019 | pmid = 32096046 | doi = 10.1007/978-981-32-9358-8_23 | isbn = 978-981-329-357-1 | s2cid = 211475911 | veditors = Takashima A, Wolozin B, Buee L | publisher = Springer | place = Singapore }}</ref> True [[prion]]s are defined by their ability to induce misfolding of native proteins to perpetuate the pathology. True prions, like [[prion protein|PRNP]], are also infectious with the capability to cross species. Since tau has yet to be proven to be infectious it is not considered to be a true prion but instead a "prion-like" protein. Much like true prions, pathological tau aggregates have been shown to have the capacity to induce misfolding of native tau protein.<ref>{{cite journal | vauthors = Bloom GS | title = Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis | journal = JAMA Neurology | volume = 71 | issue = 4 | pages = 505–508 | date = April 2014 | pmid = 24493463 | doi = 10.1001/jamaneurol.2013.5847 | doi-access = free }}</ref> Both misfolding competent and non-misfolding competent species of tau aggregates have been reported, indicating a highly specific mechanism.<ref>{{cite journal | vauthors = Hosokawa M, Hasegawa M | title = [Prion-like Propagation Model of Tau] | journal = Yakugaku Zasshi | volume = 139 | issue = 7 | pages = 1021–1025 | date = 2019-07-01 | pmid = 31257249 | doi = 10.1248/yakushi.18-00165-6 | doi-access = free }}</ref>

== Interactions ==

Tau protein has been shown to [[Protein-protein interaction|interact]] with:
* [[Alpha-synuclein]],<ref name="pmid10464279">{{cite journal | vauthors = Jensen PH, Hager H, Nielsen MS, Hojrup P, Gliemann J, Jakes R | title = alpha-synuclein binds to Tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356 | journal = The Journal of Biological Chemistry | volume = 274 | issue = 36 | pages = 25481–9 | date = September 1999 | pmid = 10464279 | doi = 10.1074/jbc.274.36.25481 | doi-access = free }}</ref><ref name="pmid14528052">{{cite journal | vauthors = Giasson BI, Lee VM, Trojanowski JQ | title = Interactions of amyloidogenic proteins | journal = Neuromolecular Medicine | volume = 4 | issue = 1–2 | pages = 49–58 | year = 2003 | pmid = 14528052 | doi = 10.1385/NMM:4:1-2:49 | s2cid = 9086733 }}</ref>
* [[FYN]],<ref name="pmid11826099">{{cite journal | vauthors = Klein C, Kramer EM, Cardine AM, Schraven B, Brandt R, Trotter J | title = Process outgrowth of oligodendrocytes is promoted by interaction of fyn kinase with the cytoskeletal protein tau | journal = The Journal of Neuroscience | volume = 22 | issue = 3 | pages = 698–707 | date = February 2002 | pmid = 11826099 | pmc = 6758498 | doi = 10.1523/JNEUROSCI.22-03-00698.2002 }}</ref>
*[[Proto-oncogene tyrosine-protein kinase Src]]
* [[S100B]],<ref name="pmid11264299">{{cite journal | vauthors = Yu WH, Fraser PE | title = S100beta interaction with tau is promoted by zinc and inhibited by hyperphosphorylation in Alzheimer's disease | journal = The Journal of Neuroscience | volume = 21 | issue = 7 | pages = 2240–6 | date = April 2001 | pmid = 11264299 | pmc = 6762409 | doi = 10.1523/JNEUROSCI.21-07-02240.2001 }}</ref><ref name="pmid2833519">{{cite journal | vauthors = Baudier J, Cole RD | title = Interactions between the microtubule-associated tau proteins and S100b regulate tau phosphorylation by the Ca2+/calmodulin-dependent protein kinase II | journal = The Journal of Biological Chemistry | volume = 263 | issue = 12 | pages = 5876–83 | date = April 1988 | doi = 10.1016/S0021-9258(18)60647-7 | pmid = 2833519 | doi-access = free }}</ref> and
* [[YWHAZ]].<ref name="pmid10840038">{{cite journal | vauthors = Hashiguchi M, Sobue K, Paudel HK | title = 14-3-3zeta is an effector of tau protein phosphorylation | journal = The Journal of Biological Chemistry | volume = 275 | issue = 33 | pages = 25247–54 | date = August 2000 | pmid = 10840038 | doi = 10.1074/jbc.M003738200 | doi-access = free }}</ref>

== See also ==
{{col div|colwidth=30em}}
* [[Tauopathy]], a class of diseases associated with accumulated tau proteins
* [[Dementia pugilistica]]
* [[Alzheimer's disease]]
* [[Primary age-related tauopathy]]
* Aging-related tau astrogliopathy
* [[Corticobasal degeneration]]
* [[Progressive supranuclear palsy]]
* [[Proteopathy]]
* [[Pick's disease]]
* [[Frontotemporal dementia and parkinsonism linked to chromosome 17]]
* [[Prion]]
{{colend}}

== References ==
{{Reflist|32em}}

== Further reading ==
{{refbegin|32em}}
* {{cite journal | vauthors = Goedert M, Crowther RA, Garner CC | title = Molecular characterization of microtubule-associated proteins tau and MAP2 | journal = Trends in Neurosciences | volume = 14 | issue = 5 | pages = 193–9 | date = May 1991 | pmid = 1713721 | doi = 10.1016/0166-2236(91)90105-4 | s2cid = 44928661 }}
* {{cite journal | vauthors = Morishima-Kawashima M, Hasegawa M, Takio K, Suzuki M, Yoshida H, Watanabe A, Titani K, Ihara Y | title = Hyperphosphorylation of tau in PHF | journal = Neurobiology of Aging | volume = 16 | issue = 3 | pages = 365–71; discussion 371–80 | year = 1995 | pmid = 7566346 | doi = 10.1016/0197-4580(95)00027-C | s2cid = 22471158 }}
* {{cite journal | vauthors = Heutink P | title = Untangling tau-related dementia | journal = Human Molecular Genetics | volume = 9 | issue = 6 | pages = 979–86 | date = April 2000 | pmid = 10767321 | doi = 10.1093/hmg/9.6.979 | url = http://repub.eur.nl/pub/9318 | doi-access = free | hdl = 1765/9318 | hdl-access = free }}
* {{cite journal | vauthors = Goedert M, Spillantini MG | title = Tau mutations in frontotemporal dementia FTDP-17 and their relevance for Alzheimer's disease | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1502 | issue = 1 | pages = 110–21 | date = July 2000 | pmid = 10899436 | doi = 10.1016/S0925-4439(00)00037-5 | doi-access = free }}
* {{cite journal | vauthors = Morishima-Kawashima M, Ihara Y | title = [Recent advances in Alzheimer's disease] | journal = Seikagaku. The Journal of Japanese Biochemical Society | volume = 73 | issue = 11 | pages = 1297–307 | date = November 2001 | pmid = 11831025 }}
* {{cite journal | vauthors = Blennow K, Vanmechelen E, Hampel H | title = CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer's disease | journal = Molecular Neurobiology | volume = 24 | issue = 1–3 | pages = 87–97 | year = 2002 | pmid = 11831556 | doi = 10.1385/MN:24:1-3:087 | s2cid = 24891421 }}
* {{cite journal | vauthors = Ingram EM, Spillantini MG | title = Tau gene mutations: dissecting the pathogenesis of FTDP-17 | journal = Trends in Molecular Medicine | volume = 8 | issue = 12 | pages = 555–62 | date = December 2002 | pmid = 12470988 | doi = 10.1016/S1471-4914(02)02440-1 }}
* {{cite journal | vauthors = Pickering-Brown S | title = The tau gene locus and frontotemporal dementia | journal = Dementia and Geriatric Cognitive Disorders | volume = 17 | issue = 4 | pages = 258–60 | year = 2004 | pmid = 15178931 | doi = 10.1159/000077149 | s2cid = 27693523 }}
* {{cite journal | vauthors = van Swieten JC, Rosso SM, van Herpen E, Kamphorst W, Ravid R, Heutink P | title = Phenotypic variation in frontotemporal dementia and parkinsonism linked to chromosome 17 | journal = Dementia and Geriatric Cognitive Disorders | volume = 17 | issue = 4 | pages = 261–4 | year = 2004 | pmid = 15178932 | doi = 10.1159/000077150 | s2cid = 36197015 }}
* {{cite journal | vauthors = Kowalska A, Jamrozik Z, Kwieciński H | title = Progressive supranuclear palsy--parkinsonian disorder with tau pathology | journal = Folia Neuropathologica | volume = 42 | issue = 2 | pages = 119–23 | year = 2004 | pmid = 15266787 }}
* {{cite journal | vauthors = Rademakers R, Cruts M, van Broeckhoven C | title = The role of tau (MAPT) in frontotemporal dementia and related tauopathies | journal = Human Mutation | volume = 24 | issue = 4 | pages = 277–95 | date = October 2004 | pmid = 15365985 | doi = 10.1002/humu.20086 | s2cid = 28578030 }}
* {{cite journal | vauthors = Lee HG, Perry G, Moreira PI, Garrett MR, Liu Q, Zhu X, Takeda A, Nunomura A, Smith MA | title = Tau phosphorylation in Alzheimer's disease: pathogen or protector? | journal = Trends in Molecular Medicine | volume = 11 | issue = 4 | pages = 164–9 | date = April 2005 | pmid = 15823754 | doi = 10.1016/j.molmed.2005.02.008 | hdl = 10316/4769 | hdl-access = free }}
* {{cite journal | vauthors = Hardy J, Pittman A, Myers A, Gwinn-Hardy K, Fung HC, de Silva R, Hutton M, Duckworth J | title = Evidence suggesting that Homo neanderthalensis contributed the H2 MAPT haplotype to Homo sapiens | journal = Biochemical Society Transactions | volume = 33 | issue = Pt 4 | pages = 582–5 | date = August 2005 | pmid = 16042549 | doi = 10.1042/BST0330582 }}
* {{cite journal | vauthors = Deutsch SI, Rosse RB, Lakshman RM | title = Dysregulation of tau phosphorylation is a hypothesized point of convergence in the pathogenesis of alzheimer's disease, frontotemporal dementia and schizophrenia with therapeutic implications | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 30 | issue = 8 | pages = 1369–80 | date = December 2006 | pmid = 16793187 | doi = 10.1016/j.pnpbp.2006.04.007 | s2cid = 6848053 }}
* {{cite journal | vauthors = Williams DR | title = Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau | journal = Internal Medicine Journal | volume = 36 | issue = 10 | pages = 652–60 | date = October 2006 | pmid = 16958643 | doi = 10.1111/j.1445-5994.2006.01153.x | s2cid = 19357113 }}
* {{cite journal | vauthors = Pittman AM, Fung HC, de Silva R | title = Untangling the tau gene association with neurodegenerative disorders | journal = Human Molecular Genetics | volume = 15 Spec No 2 | issue = Review Issue 2 | pages = R188-95 | date = October 2006 | pmid = 16987883 | doi = 10.1093/hmg/ddl190 | series = 15 | doi-access = free }}
* {{cite journal | vauthors = Roder HM, Hutton ML | title = Microtubule-associated protein tau as a therapeutic target in neurodegenerative disease | journal = Expert Opinion on Therapeutic Targets | volume = 11 | issue = 4 | pages = 435–42 | date = April 2007 | pmid = 17373874 | doi = 10.1517/14728222.11.4.435 | s2cid = 36430988 }}
* {{cite journal | vauthors = van Swieten J, Spillantini MG | title = Hereditary frontotemporal dementia caused by Tau gene mutations | journal = Brain Pathology | volume = 17 | issue = 1 | pages = 63–73 | date = January 2007 | pmid = 17493040 | doi = 10.1111/j.1750-3639.2007.00052.x | s2cid = 40879765 | pmc = 8095608 }}
* {{cite journal | vauthors = Caffrey TM, Wade-Martins R | title = Functional MAPT haplotypes: bridging the gap between genotype and neuropathology | journal = Neurobiology of Disease | volume = 27 | issue = 1 | pages = 1–10 | date = July 2007 | pmid = 17555970 | pmc = 2801069 | doi = 10.1016/j.nbd.2007.04.006 }}
* {{cite journal | vauthors = Delacourte A | title = Tauopathies: recent insights into old diseases | journal = Folia Neuropathologica | volume = 43 | issue = 4 | pages = 244–57 | year = 2005 | pmid = 16416389 }}
* {{cite journal | vauthors = Hirokawa N, Shiomura Y, Okabe S | title = Tau proteins: the molecular structure and mode of binding on microtubules | journal = The Journal of Cell Biology | volume = 107 | issue = 4 | pages = 1449–59 | date = October 1988 | pmid = 3139677 | pmc = 2115262 | doi = 10.1083/jcb.107.4.1449 }}
{{refend}}

==External links==
{{Commons category|Tau proteins}}
{{Wiktionary|tau protein|tau}}

*{{MeshName|tau+Proteins}}
*[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=ftdp-17 GeneReviews/NCBI/NIH/UW entry on MAPT-Related Disorders]
*[https://web.archive.org/web/20131203022442/http://rad.usuhs.edu/medpix/kiosk_image.html?mode=pt&pt_id=13421#pic MR scans of variant CJD] CSF tau-positive man
*{{PDBe-KB2|P10636|Microtubule-associated protein tau}}

{{Cytoskeletal Proteins}}

{{DEFAULTSORT:Tau Protein}}
[[Category:Proteins]]