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Published: 10 December 2022
Last updated: 28 January 2023

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1

LITERSKY, Joel M., Gail V. W. JOHNSON, Ross JAKES, Michel GOEDERT, Michael LEE, and Peter SEUBERT. "Tau protein is phosphorylated by cyclic AMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II within its microtubule-binding domains at Ser-262 and Ser-356." Biochemical Journal 316, no. 2 (June 1, 1996): 655–60. http://dx.doi.org/10.1042/bj3160655.

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Phosphorylation of tau protein at Ser-262 has been shown to diminish its ability to bind to taxol-stabilized microtubules. The paired helical filaments (PHFs) found in Alzheimer's disease brain are composed of PHF-tau, which is hyperphosphorylated at multiple sites including Ser-262. However, protein kinase(s) able to phosphorylate this site are still under investigation. In this study, the ability of cyclic AMP-dependent protein kinase (cAMP-PK) and calcium/calmodulin-dependent protein kinase II (CaMKII) to phosphorylate tau at Ser-262, as well as Ser-356, is demonstrated by use of a monoclonal antibody (12E8) which has been shown to recognize tau when these sites are phosphorylated. Cleavage of cAMP-PK-phosphorylated tau at cysteine residues by 2-nitro-5-thiocyanobenzoic acid, which cuts the protein into essentially two fragments and separates Ser-262 from Ser-356, revealed that cAMP-PK phosphorylates both Ser-262 and Ser-356. In addition, phosphorylation with cAMP-PK or CaMKII of recombinant tau in which Ser-262, Ser-356 or both had been mutated to alanines, clearly demonstrated that cAMP-PK and CaMKII were able to phosphorylate both sites. Mitogen-activated protein kinase or protein kinase C did not phosphorylate tau at Ser-262 and/or Ser-356. Finally, evidence is presented that phosphorylation of both these sites occurs in cultured nerve cells under certain conditions, indicating their potential physiological relevance.
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2

Sen, Tanusree, Pampa Saha, Tong Jiang, and Nilkantha Sen. "Sulfhydration of AKT triggers Tau-phosphorylation by activating glycogen synthase kinase 3β in Alzheimer’s disease." Proceedings of the National Academy of Sciences 117, no. 8 (February 12, 2020): 4418–27. http://dx.doi.org/10.1073/pnas.1916895117.

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In Alzheimer’s disease (AD), human Tau is phosphorylated at S199 (hTau-S199-P) by the protein kinase glycogen synthase kinase 3β (GSK3β). HTau-S199-P mislocalizes to dendritic spines, which induces synaptic dysfunction at the early stage of AD. The AKT kinase, once phosphorylated, inhibits GSK3β by phosphorylating it at S9. In AD patients, the abundance of phosphorylated AKT with active GSK3β implies that phosphorylated AKT was unable to inactivate GSK3β. However, the underlying mechanism of the inability of phosphorylated AKT to phosphorylate GSK3β remains unknown. Here, we show that total AKT and phosphorylated AKT was sulfhydrated at C77 due to the induction of intracellular hydrogen sulfide (H2S). The increase in intracellular H2S levels resulted from the induction of the proinflammatory cytokine, IL-1β, which is a pathological hallmark of AD. Sulfhydrated AKT does not interact with GSK3β, and therefore does not phosphorylate GSK3β. Thus, active GSK3β phosphorylates Tau aberrantly. In a transgenic knockin mouse (AKT-KI+/+) that lacked sulfhydrated AKT, the interaction between AKT or phospho-AKT with GSK3β was restored, and GSK3β became phosphorylated. In AKT-KI+/+ mice, expressing the pathogenic human Tau mutant (hTau-P301L), the hTau S199 phosphorylation was ameliorated as GSK3β phosphorylation was regained. This event leads to a decrease in dendritic spine loss by reducing dendritic localization of hTau-S199-P, which improves cognitive dysfunctions. Sulfhydration of AKT was detected in the postmortem brains from AD patients; thus, it represents a posttranslational modification of AKT, which primarily contributes to synaptic dysfunction in AD.
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3

Goedert, Michel. "Pinning down phosphorylated tau." Nature 399, no. 6738 (June 1999): 739–40. http://dx.doi.org/10.1038/21550.

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4

陈, 亦刚. "Abnormally Phosphorylated Tau and Tauopathies." International Journal of Psychiatry and Neurology 06, no. 02 (2017): 7–12. http://dx.doi.org/10.12677/ijpn.2017.62002.

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5

WOODS, Yvonne L., Philip COHEN, Walter BECKER, Ross JAKES, Michel GOEDERT, Xuemin WANG, and Christopher G. PROUD. "The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bɛ at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase." Biochemical Journal 355, no. 3 (April 24, 2001): 609–15. http://dx.doi.org/10.1042/bj3550609.

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The substrate specificity of glycogen synthase kinase 3 (GSK3) is unusual in that efficient phosphorylation only occurs if another phosphoserine or phosphothreonine residue is already present four residues C-terminal to the site of GSK3 phosphorylation. One such substrate is the ε-subunit of rat eukaryotic protein-synthesis initiation factor 2B (eIF2Bε), which is inhibited by the GSK3-catalysed phosphorylation of Ser535. There is evidence that GSK3 is only able to phosphorylate eIF2Bε at Ser535 if Ser539 is already phosphorylated by another protein kinase. However, no protein kinases capable of phosphorylating Ser539 have so far been identified. Here we show that Ser539 of eIF2Bε, which is followed by proline, is phosphorylated specifically by two isoforms of dual-specificity tyrosine phosphorylated and regulated kinase (DYRK2 and DYRK1A), but only weakly or not at all by other ‘proline-directed’ protein kinases tested. We also establish that phosphorylation of Ser539 permits GSK3 to phosphorylate Ser535in vitro and that eIF2Bε is highly phosphorylated at Ser539in vivo. The DYRK isoforms also phosphorylate human microtubule-associated protein tau at Thr212in vitro, a residue that is phosphorylated in foetal tau and hyperphosphorylated in filamentous tau from Alzheimer's-disease brain. Phosphorylation of Thr212 primes tau for phosphorylation by GSK3 at Ser208in vitro, suggesting a more general role for DYRK isoforms in priming phosphorylation of GSK3 substrates.
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6

Anderton, Brian H., Joanna Betts, Walter P. Blackstock, Jean-Pierre Brion, Sara Chapman, James Connell, Rejith Dayanandan, et al. "Sites of phosphorylation in tau and factors affecting their regulation." Biochemical Society Symposia 67 (February 1, 2001): 73–80. http://dx.doi.org/10.1042/bss0670073.

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The microtubule-associated protein, tau, is the principal component of paired helical filaments (PHFs) in Alzheimer's disease. PHF-tau is highly phosphorylated and a total of 25 sites of phosphorylation have so far been identified. Many of these sites are serine or threonine residues that are immediately followed in the sequence by proline residues, and hence are candidate phosphorylation sites for proline-directed kinases. In vitro, glycogen synthase kinase-3 (GSK-3), extracellular signal-related kinase-1 and -2, and mitogen-activated protein kinases, p38 kinase and c-jun N-terminal kinase, all phosphorylate many of these sites, although with different efficiencies for particular sites. Phosphorylation studies in transfected cells and neurons show that GSK-3 phosphorylates tau more extensively than do these other proline-directed kinases. Mutations in tau have been shown to affect in vitro phosphorylation of tau by GSK-3. The Arg406-->Trp (R406W) tau mutation also affects tau phosphorylation in cells.
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7

Arai, Tetsuaki, Jian-Ping Guo, and Patrick L. McGeer. "Proteolysis of Non-phosphorylated and Phosphorylated Tau by Thrombin." Journal of Biological Chemistry 280, no. 7 (November 12, 2004): 5145–53. http://dx.doi.org/10.1074/jbc.m409234200.

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8

Goedert, M., R. Jakes, R. A. Crowther, P. Cohen, E. Vanmechelen, M. Vandermeeren, and P. Cras. "Epitope mapping of monoclonal antibodies to the paired helical filaments of Alzheimer's disease: identification of phosphorylation sites in tau protein." Biochemical Journal 301, no. 3 (August 1, 1994): 871–77. http://dx.doi.org/10.1042/bj3010871.

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Tau is a neuronal phosphoprotein the expression of which is developmentally regulated. A single tau isoform is expressed in fetal human brain but six isoforms are expressed in adult human brain, with the fetal isoform corresponding to the shortest adult isoform. Phosphorylation is also developmentally regulated, as fetal tau is phosphorylated at more sites than adult tau. In Alzheimer's disease, the six adult tau isoforms become hyperphosphorylated and form the paired helical filament (PHF), the major fibrous component of the neurofibrillary lesions. One way to identify phosphorylated sites in tau is to use antibodies that recognize phosphorylated residues within a specific amino acid sequence. We here characterize the two novel phosphorylation-dependent anti-tau antibodies AT270 and AT180 and identify their epitopes as containing phosphorylated Thr-181 and Thr-231 respectively. With these antibodies we show that these two threonine residues are partially phosphorylated in fetal and adult tau and almost fully phosphorylated in PHF tau. This result contrasts with previous studies of Ser-202 and Ser-396 which are partially phosphorylated in fetal tau, unphosphorylated in adult tau but almost fully phosphorylated in PHF tau.
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9

Drummond, Eleanor, Geoffrey Pires, Claire MacMurray, Manor Askenazi, Shruti Nayak, Marie Bourdon, Jiri Safar, Beatrix Ueberheide, and Thomas Wisniewski. "Phosphorylated tau interactome in the human Alzheimer’s disease brain." Brain 143, no. 9 (August 19, 2020): 2803–17. http://dx.doi.org/10.1093/brain/awaa223.

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Abstract Accumulation of phosphorylated tau is a key pathological feature of Alzheimer’s disease. Phosphorylated tau accumulation causes synaptic impairment, neuronal dysfunction and formation of neurofibrillary tangles. The pathological actions of phosphorylated tau are mediated by surrounding neuronal proteins; however, a comprehensive understanding of the proteins that phosphorylated tau interacts with in Alzheimer’s disease is surprisingly limited. Therefore, the aim of this study was to determine the phosphorylated tau interactome. To this end, we used two complementary proteomics approaches: (i) quantitative proteomics was performed on neurofibrillary tangles microdissected from patients with advanced Alzheimer’s disease; and (ii) affinity purification-mass spectrometry was used to identify which of these proteins specifically bound to phosphorylated tau. We identified 542 proteins in neurofibrillary tangles. This included the abundant detection of many proteins known to be present in neurofibrillary tangles such as tau, ubiquitin, neurofilament proteins and apolipoprotein E. Affinity purification-mass spectrometry confirmed that 75 proteins present in neurofibrillary tangles interacted with PHF1-immunoreactive phosphorylated tau. Twenty-nine of these proteins have been previously associated with phosphorylated tau, therefore validating our proteomic approach. More importantly, 34 proteins had previously been associated with total tau, but not yet linked directly to phosphorylated tau (e.g. synaptic protein VAMP2, vacuolar-ATPase subunit ATP6V0D1); therefore, we provide new evidence that they directly interact with phosphorylated tau in Alzheimer’s disease. In addition, we also identified 12 novel proteins, not previously known to be physiologically or pathologically associated with tau (e.g. RNA binding protein HNRNPA1). Network analysis showed that the phosphorylated tau interactome was enriched in proteins involved in the protein ubiquitination pathway and phagosome maturation. Importantly, we were able to pinpoint specific proteins that phosphorylated tau interacts with in these pathways for the first time, therefore providing novel potential pathogenic mechanisms that can be explored in future studies. Combined, our results reveal new potential drug targets for the treatment of tauopathies and provide insight into how phosphorylated tau mediates its toxicity in Alzheimer’s disease.
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10

Tseng, H. C., Q. Lu, E. Henderson, and D. J. Graves. "Phosphorylated tau can promote tubulin assembly." Proceedings of the National Academy of Sciences 96, no. 17 (August 17, 1999): 9503–8. http://dx.doi.org/10.1073/pnas.96.17.9503.

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11

Lim, Jormay, and Kun Ping Lu. "Pinning down phosphorylated tau and tauopathies." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1739, no. 2-3 (January 2005): 311–22. http://dx.doi.org/10.1016/j.bbadis.2004.10.003.

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12

Kosik, Kenneth S., and Hideki Shimura. "Phosphorylated tau and the neurodegenerative foldopathies." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1739, no. 2-3 (January 2005): 298–310. http://dx.doi.org/10.1016/j.bbadis.2004.10.011.

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13

Zhang, Shengnan, Chuchu Wang, Jinxia Lu, Xiaojuan Ma, Zhenying Liu, Dan Li, Zhijun Liu, and Cong Liu. "In-Cell NMR Study of Tau and MARK2 Phosphorylated Tau." International Journal of Molecular Sciences 20, no. 1 (December 26, 2018): 90. http://dx.doi.org/10.3390/ijms20010090.

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The intrinsically disordered protein, Tau, is abundant in neurons and contributes to the regulation of the microtubule (MT) and actin network, while its intracellular abnormal aggregation is closely associated with Alzheimer’s disease. Here, using in-cell Nuclear Magnetic Resonance (NMR) spectroscopy, we investigated the conformations of two different isoforms of Tau, Tau40 and k19, in mammalian cells. Combined with immunofluorescence imaging and western blot analyses, we found that the isotope-enriched Tau, which was delivered into the cultured mammalian cells by electroporation, is partially colocalized with MT and actin filaments (F-actin). We acquired the NMR spectrum of Tau in human embryonic kidney 293 (HEK-293T) cells, and compared it with the NMR spectra of Tau added with MT, F-actin, and a variety of crowding agents, respectively. We found that the NMR spectrum of Tau in complex with MT best recapitulates the in-cell NMR spectrum of Tau, suggesting that Tau predominantly binds to MT at its MT-binding repeats in HEK-293T cells. Moreover, we found that disease-associated phosphorylation of Tau was immediately eliminated once phosphorylated Tau was delivered into HEK-293T cells, implying a potential cellular protection mechanism under stressful conditions. Collectively, the results of our study reveal that Tau utilizes its MT-binding repeats to bind MT in mammalian cells and highlight the potential of using in-cell NMR to study protein structures at the residue level in mammalian cells.
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14

Seubert, Peter, Madhumalti Mawal-Dewan, Robin Barbour, Ross Jakes, Michel Goedert, Gail V. W. Johnson, Joel M. Litersky, et al. "Detection of Phosphorylated Ser262in Fetal Tau, Adult Tau, and Paired Helical Filament Tau." Journal of Biological Chemistry 270, no. 32 (August 11, 1995): 18917–22. http://dx.doi.org/10.1074/jbc.270.32.18917.

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15

Puvenna, Vikram, Madeline Engeler, Manoj Banjara, Chanda Brennan, Peter Schreiber, Aaron Dadas, Ashkon Bahrami, et al. "Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy." Brain Research 1630 (January 2016): 225–40. http://dx.doi.org/10.1016/j.brainres.2015.11.007.

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16

Ishiguro, K., J. Park, M. Takamatsu, S. Yonekura, N. Sahara, H. Mori, T. Uchida, and K. Imahori. "511 Tau protein kinases and phosphorylated tau protein in human brain." Neurobiology of Aging 17, no. 4 (January 1996): S127. http://dx.doi.org/10.1016/s0197-4580(96)80513-6.

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17

Shults, Nataliia V., Sarah Seeherman, Nurefsan E. Sariipek, Vladyslava Rybka, Lucia Marcocci, Sergiy G. Gychka, Yasmine F. Ibrahim, and Yuichiro J. Suzuki. "Tau Protein in Lung Smooth Muscle Cells." Journal of Respiration 1, no. 1 (November 29, 2020): 30–39. http://dx.doi.org/10.3390/jor1010003.

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Tau, a microtubule-associated protein, plays a critical role in the pathophysiology of neurons. However, whether tau protein is expressed in smooth muscle cells is unknown. Thus, we tested the hypothesis that tau protein is expressed in the primary cultures of smooth muscle cells. Here, we report that tau protein is expressed and constitutively phosphorylated at threonine 181 in various smooth muscle cell types, including human pulmonary artery smooth muscle cells, bronchial airway smooth muscle cells, and cerebral artery smooth muscle cells. Immunofluorescence staining revealed that phosphorylated tau at threonine 181 is more organized in the cell than is total tau protein. A protein phosphatase inhibitor, calyculin A, induced the formation of higher molecular weight species of phosphorylated tau, as visualized by Western blotting, indicating the occurrence of tau aggregation. Immunofluorescence analysis also showed that calyculin A caused the aggregation of phosphorylated tau and disrupted the cytoskeletal organization. These results demonstrate the existence of tau protein in smooth muscle cells, and that smooth muscle tau is susceptible to protein phosphorylation and aggregation. Lung smooth muscle tau may therefore play an important role in pulmonary pathophysiology.
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18

Rawat, Priyanka, Ujala Sehar, Jasbir Bisht, Ashley Selman, John Culberson, and P. Hemachandra Reddy. "Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies." International Journal of Molecular Sciences 23, no. 21 (October 25, 2022): 12841. http://dx.doi.org/10.3390/ijms232112841.

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Alzheimer’s disease (AD) is the leading cause of dementia in elderly people. Amyloid beta (Aβ) deposits and neurofibrillary tangles are the major pathological features in an Alzheimer’s brain. These proteins are highly expressed in nerve cells and found in most tissues. Tau primarily provides stabilization to microtubules in the part of axons and dendrites. However, tau in a pathological state becomes hyperphosphorylated, causing tau dysfunction and leading to synaptic impairment and degeneration of neurons. This article presents a summary of the role of tau, phosphorylated tau (p-tau) in AD, and other tauopathies. Tauopathies, including Pick’s disease, frontotemporal dementia, corticobasal degeneration, Alzheimer’s disease, argyrophilic grain disease, progressive supranuclear palsy, and Huntington’s disease, are the result of misprocessing and accumulation of tau within the neuronal and glial cells. This article also focuses on current research on the post-translational modifications and genetics of tau, tau pathology, the role of tau in tauopathies and the development of new drugs targeting p-tau, and the therapeutics for treating and possibly preventing tauopathies.
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19

Jack, Clifford R. "The transformative potential of plasma phosphorylated tau." Lancet Neurology 19, no. 5 (May 2020): 373–74. http://dx.doi.org/10.1016/s1474-4422(20)30112-5.

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20

Iqbal, K., C. X. Gong, T. J. Singh, and I. Grundke-Iqbal. "ABNORMALLY PHOSPHORYLATED TAU IN ALZHEIMER DISEASE BRAIN." Journal of Neuropathology and Experimental Neurology 52, no. 3 (May 1993): 266. http://dx.doi.org/10.1097/00005072-199305000-00023.

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21

Brion, Jean-Pierre, Brian H. Anderton, Michéle Authelet, Rejith Dayanandan, Karelle Leroy, Simon Lovestone, Jean-Noël Octave, Laurent Pradier, Nicole Touchet, and Günter Tremp. "Neurofibrillary tangles and tau phosphorylation." Biochemical Society Symposia 67 (February 1, 2001): 81–88. http://dx.doi.org/10.1042/bss0670081.

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Neurofibrillary tangles (NFTs) are a characteristic neuropathological lesion of Alzheimer's disease (AD). They are composed of a highly-phosphorylated form of the microtubule-associated protein tau. We are investigating the relationship between NFTs and microtubule stability and how tau phosphorylation and function is affected in transgenic models and by co-expression with ϐ-amyloid precursor protein and presenilins. In most NFT-bearing neurons, we observed a strong reduction in acetylated α-tubulin immunoreactivity (a marker of stable microtubules) and a reduction of the in situ hybridization signal for tubulin mRNA. In transfected cells, mutated tau forms (corresponding to tau mutations identified in familial forms of frontotemporal dementias linked to chromosome 17) were less efficient in their ability to sustain microtubule growth. These observations are consistent with the hypothesis that destabilization of the microtubule network is an important mechanism of cell dysfunction in Alzheimer's disease. The glycogen synthase kinase-3 ϐ (GSK-3ϐ) generates many phosphorylated sites on tau. We performed a neuroanatomical study of GSK-3ϐ distribution showing that developmental evolution of GSK-3ϐ compartmentalization in neurons paralleled that of phosphorylated tau. Studies on transfected cells and on cultured neurons showed that GSK-3 ϐ activity controls tau phosphorylation and tau functional interaction with microtubules. Tau phosphorylation was not affected in neurons overexpressing ϐ-amyloid precursor protein. Transgenic mice expressing a human tau isoform and double transgenic animals for tau and mutated presenilin 1 have been generated; a somatodendritic accumulation of phosphorylated transgenic tau proteins, as observed in the pretangle stage in AD, has been observed but NFTs were not found, suggesting that additional factors might be necessary to induce their formation.
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22

UTTON, Michelle A., André VANDECANDELAERE, Uta WAGNER, C. Hugh REYNOLDS, Graham M. GIBB, Christopher C. J. MILLER, Peter M. BAYLEY, and Brian H. ANDERTON. "Phosphorylation of tau by glycogen synthase kinase 3β affects the ability of tau to promote microtubule self-assembly." Biochemical Journal 323, no. 3 (May 1, 1997): 741–47. http://dx.doi.org/10.1042/bj3230741.

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To study the effects of phosphorylation by glycogen synthase kinase-3β (GSK-3β) on the ability of the microtubule-associated protein tau to promote microtubule self-assembly, tau isoform 1 (foetal tau) and three mutant forms of this tau isoform were investigated. The three mutant forms of tau had the following serine residues, known to be phosphorylated by GSK-3, replaced with alanine residues so as to preclude their phosphorylation: (1) Ser-199 and Ser-202 (Ser-199/202 → Ala), (2) Ser-235 (Ser-235 → Ala) and (3) Ser-396 and Ser-404 (Ser-396/404 → Ala). Wild-type tau and the mutant forms of tau were phosphorylated with GSK-3β, and their ability to promote microtubule self-assembly was compared with the corresponding non-phosphorylated tau species. In the non-phosphorylated form, wild-type tau and all of the mutants affected the mean microtubule length and number concentrations of assembled microtubules in a manner consistant with enhanced microtubule nucleation. Phosphorylation of these tau species with GSK-3β consistently reduced the ability of a given tau species to promote microtubule self-assembly, although the affinity of the tau for the microtubules was not greatly affected by phosphorylation since the tau species remained largely associated with the microtubules. This suggests that the regulation of microtubule assembly can be controlled by phosphorylation of tau at sites accessible to GSK-3β by a mechanism that does not necessarily involve the dissociation of tau from the microtubules.
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23

Oba, Toshiya, Taro Saito, Akiko Asada, Sawako Shimizu, Koichi M. Iijima, and Kanae Ando. "Microtubule affinity–regulating kinase 4 with an Alzheimer's disease-related mutation promotes tau accumulation and exacerbates neurodegeneration." Journal of Biological Chemistry 295, no. 50 (October 5, 2020): 17138–47. http://dx.doi.org/10.1074/jbc.ra120.014420.

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Accumulation of the microtubule-associated protein tau is associated with Alzheimer's disease (AD). In AD brain, tau is abnormally phosphorylated at many sites, and phosphorylation at Ser-262 and Ser-356 plays critical roles in tau accumulation and toxicity. Microtubule affinity–regulating kinase 4 (MARK4) phosphorylates tau at those sites, and a double de novo mutation in the linker region of MARK4, ΔG316E317D, is associated with an elevated risk of AD. However, it remains unclear how this mutation affects phosphorylation, aggregation, and accumulation of tau and tau-induced neurodegeneration. Here, we report that MARK4ΔG316E317D increases the abundance of highly phosphorylated, insoluble tau species and exacerbates neurodegeneration via Ser-262/356–dependent and –independent mechanisms. Using transgenic Drosophila expressing human MARK4 (MARK4wt) or a mutant version of MARK4 (MARK4ΔG316E317D), we found that coexpression of MARK4wt and MARK4ΔG316E317D increased total tau levels and enhanced tau-induced neurodegeneration and that MARK4ΔG316E317D had more potent effects than MARK4wt. Interestingly, the in vitro kinase activities of MARK4wt and MARK4ΔG316E317D were similar. When tau phosphorylation at Ser-262 and Ser-356 was blocked by alanine substitutions, MARK4wt did not promote tau accumulation or exacerbate neurodegeneration, whereas coexpression of MARK4ΔG316E317D did. Both MARK4wt and MARK4ΔG316E317D increased the levels of oligomeric forms of tau; however, only MARK4ΔG316E317D further increased the detergent insolubility of tau in vivo. Together, these findings suggest that MARK4ΔG316E317D increases tau levels and exacerbates tau toxicity via a novel gain-of-function mechanism and that modification in this region of MARK4 may affect disease pathogenesis.
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24

Preuss, U., F. Döring, S. Illenberger, and E. M. Mandelkow. "Cell cycle-dependent phosphorylation and microtubule binding of tau protein stably transfected into Chinese hamster ovary cells." Molecular Biology of the Cell 6, no. 10 (October 1995): 1397–410. http://dx.doi.org/10.1091/mbc.6.10.1397.

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Tau protein, a neuronal microtubule-associated protein, is phosphorylated in situ and hyperphosphorylated when aggregated into the paired helical filaments of Alzheimer's disease. To study the phosphorylation of tau protein in vivo, we have stably transfected htau40, the largest human tau isoform, into Chinese hamster ovary cells. The distribution and phosphorylation of tau was monitored by gel shift, autoradiography, immunofluorescence, and immunoblotting, using the antibodies Tau-1, AT8, AT180, and PHF-1, which are sensitive to the phosphorylation of Ser202, Thr205, Thr231, Ser235, Ser396, and Ser404 and are used in the diagnosis of Alzheimer tau. In interphase cells, tau becomes phosphorylated to some extent, partly at these sites; most of the tau is associated with microtubules. In mitosis, the above Ser/Thr-Pro sites become almost completely phosphorylated, causing a pronounced shift in M(r) and an antibody reactivity similar to that of Alzheimer tau. Moreover, a substantial fraction of tau is found in the cytoplasm detached from microtubules. Autoradiographs of metabolically labeled Chinese hamster ovary cells in interphase and mitosis confirmed that tau protein is more highly phosphorylated during mitosis. The understanding of tau phosphorylation under physiological conditions might help elucidate possible mechanisms for the hyperphosphorylation in Alzheimer's disease.
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25

Herukka, Sanna-Kaisa, Corina Pennanen, Hilkka Soininen, and Tuula Pirttilä. "CSF Aβ42, Tau and Phosphorylated Tau Correlate with Medial Temporal Lobe Atrophy." Journal of Alzheimer's Disease 14, no. 1 (May 9, 2008): 51–57. http://dx.doi.org/10.3233/jad-2008-14105.

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26

Aerts, M. B., R. A. J. Esselink, B. R. Bloem, and M. M. Verbeek. "Cerebrospinal fluid tau and phosphorylated tau protein are elevated in corticobasal syndrome." Movement Disorders 26, no. 1 (September 10, 2010): 169–73. http://dx.doi.org/10.1002/mds.23341.

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27

Niu, Jiahui, Khalid Iqbal, Fei Liu, and Wen Hu. "Rats Display Sexual Dimorphism in Phosphorylation of Brain Tau with Age." Journal of Alzheimer's Disease 82, no. 2 (July 21, 2021): 855–69. http://dx.doi.org/10.3233/jad-210341.

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Background: Women have a two-fold higher risk than men to Alzheimer’s disease (AD) at midlife. Larger brain tau burden was consistently shown in older women than age-matched men. The biological basis for this gender disparity remains elusive. Objective: We sought to know whether tau expression and phosphorylation physiologically differ between males and females. Methods: We used western blots and immunohistochemistry to compare the levels of total tau and phosphorylated tau in the hippocampus and entorhinal cortex (EC) between sexes in Wistar rats at 40 days, and 8 and 20 months of age. Results: We detected no statistically significant difference in total tau, 3R-tau, and 4R-tau between sexes. However, female rats exhibited lower levels of tau unphosphorylated at the Tau-1 site at 40 days of age. At 8 months of age, females showed higher levels of tau phosphorylated at Ser190, Ser387, and Ser395 (Ser199, Ser396, and Ser404 of human tau, respectively) than males in EC. At 20 months of age, both brain regions of female rats consistently showed higher levels than males of tau phosphorylated at Ser253, Ser387, PHF-1 (Ser387/395), and Ser413 sites, which correspond to Ser262, Ser396, Ser396/404, and Ser422 of human tau, respectively. Conclusion: Rats of both sexes have comparable levels of total tau, 3R-tau, and 4R-tau, whereas females exhibit higher levels of tau phosphorylated at multiple sites that are implicated in AD tau pathology, indicating a sexual dimorphism of tau phosphorylation that may potentially underlie the disparity in brain tau burden and risk for AD between sexes.
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28

Paudel, Hemant K. "The Regulatory Ser262 of Microtubule-associated Protein Tau Is Phosphorylated by Phosphorylase Kinase." Journal of Biological Chemistry 272, no. 3 (January 1996): 1777–85. http://dx.doi.org/10.1016/s0021-9258(19)67481-8.

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29

Loeffler, David A., Lynnae M. Smith, Andrea C. Klaver, and Sanela Martić. "Effects of antibodies to phosphorylated and non-phosphorylated tau on in vitro tau phosphorylation at Serine-199: Preliminary report." Experimental Gerontology 67 (July 2015): 15–18. http://dx.doi.org/10.1016/j.exger.2015.04.010.

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30

Cousins, Katheryn A. Q., David J. Irwin, David A. Wolk, Edward B. Lee, Leslie M. J. Shaw, John Q. Trojanowski, Fulvio Da Re, Garrett S. Gibbons, Murray Grossman, and Jeffrey S. Phillips. "ATN status in amnestic and non-amnestic Alzheimer’s disease and frontotemporal lobar degeneration." Brain 143, no. 7 (July 1, 2020): 2295–311. http://dx.doi.org/10.1093/brain/awaa165.

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Abstract Under the ATN framework, CSF analytes provide evidence of the presence or absence of Alzheimer’s disease pathological hallmarks: amyloid plaques (A), phosphorylated tau (T), and accompanying neurodegeneration (N). Still, differences in CSF levels across amnestic and non-amnestic variants or due to co-occurring pathologies might lead to misdiagnoses. We assess the diagnostic accuracy of CSF markers for amyloid, tau, and neurodegeneration in an autopsy cohort of 118 Alzheimer’s disease patients (98 amnestic; 20 non-amnestic) and 64 frontotemporal lobar degeneration patients (five amnestic; 59 non-amnestic). We calculated between-group differences in CSF concentrations of amyloid-β1–42 peptide, tau protein phosphorylated at threonine 181, total tau, and the ratio of phosphorylated tau to amyloid-β1–42. Results show that non-amnestic Alzheimer’s disease patients were less likely to be correctly classified under the ATN framework using independent, published biomarker cut-offs for positivity. Amyloid-β1–42 did not differ between amnestic and non-amnestic Alzheimer’s disease, and receiver operating characteristic curve analyses indicated that amyloid-β1–42 was equally effective in discriminating both groups from frontotemporal lobar degeneration. However, CSF concentrations of phosphorylated tau, total tau, and the ratio of phosphorylated tau to amyloid-β1–42 were significantly lower in non-amnestic compared to amnestic Alzheimer’s disease patients. Receiver operating characteristic curve analyses for these markers showed reduced area under the curve when discriminating non-amnestic Alzheimer’s disease from frontotemporal lobar degeneration, compared to discrimination of amnestic Alzheimer’s disease from frontotemporal lobar degeneration. In addition, the ATN framework was relatively insensitive to frontotemporal lobar degeneration, and these patients were likely to be classified as having normal biomarkers or biomarkers suggestive of primary Alzheimer’s disease pathology. We conclude that amyloid-β1–42 maintains high sensitivity to A status, although with lower specificity, and this single biomarker provides better sensitivity to non-amnestic Alzheimer’s disease than either the ATN framework or the phosphorylated-tau/amyloid-β1–42 ratio. In contrast, T and N status biomarkers differed between amnestic and non-amnestic Alzheimer’s disease; standard cut-offs for phosphorylated tau and total tau may thus result in misclassifications for non-amnestic Alzheimer’s disease patients. Consideration of clinical syndrome may help improve the accuracy of ATN designations for identifying true non-amnestic Alzheimer’s disease.
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Jahanshahi, M., E. Nikmahzar, and S. Gorgani. "Taurine can Decrease Phosphorylated Tau Protein Levels in Alzheimer’s Model Rats’ Brains." Kathmandu University Medical Journal 19, no. 2 (June 30, 2021): 200–204. http://dx.doi.org/10.3126/kumj.v19i2.49646.

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Background Microtubule formation is a dynamic process and Tau proteins promote the assembly of tubulin monomers into microtubules. Hyperphosphorylation of some amino acids in tau proteins causes neuron starvation and finally cell death. Taurine is found in the brain and has neuroprotective effects. Objective Since the protective and therapeutic effects of Taurine on phosphorylated tau proteins level in the cerebellum and prefrontal cortex of rats induced by scopolamine have not been studied, we examined these effects. Method Adult male Wistar rats were randomly distributed into nine groups. For two weeks, Taurine-treated rats received different doses of Taurine (25, 50, and 100 mg/kg/ day) before or after scopolamine injection. The phosphorylated tau protein level in the cerebellum and prefrontal cortex was determined by the enzyme-linked immunosorbent assay (ELISA) technique. Result Pretreatment with three doses of Taurine significantly decreased the phosphorylated tau protein level that increased by scopolamine in the prefrontal cortex (p < 0.001), as well as the cerebellum (p < 0.001). Moreover, high-dose administration of Taurine (100 mg/kg/day) after scopolamine injection significantly decreased phosphorylated tau protein level in the cerebellum (p < 0.01), as well as the prefrontal cortex (p < 0.05). However, there was not any significant change in the level of phosphorylated tau protein after Taurine treatment (25 and 50 mg/kg/day) in the cerebellum and prefrontal cortex. Conclusion It can be concluded that Taurine could attenuate the increase in phosphorylated tau protein induced by scopolamine in the brain of rats and usage of Taurine as a pretreatment complement could be more useful in the protection of neurons.
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32

Song, Liqing, Daniel E. Oseid, Evan A. Wells, and Anne Skaja Robinson. "The Interplay between GSK3β and Tau Ser262 Phosphorylation during the Progression of Tau Pathology." International Journal of Molecular Sciences 23, no. 19 (October 1, 2022): 11610. http://dx.doi.org/10.3390/ijms231911610.

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Tau hyperphosphorylation has been linked directly to the formation of toxic neurofibrillary tangles (NFTs) in tauopathies, however, prior to NFT formation, the sequence of pathological events involving tau phosphorylation remains unclear. Here, the effect of glycogen synthase kinase 3β (GSK3β) on tau pathology was examined independently for each step of transcellular propagation; namely, tau intracellular aggregation, release, cellular uptake and seeding activity. We find that overexpression of GSK3β-induced phosphorylated 0N4R tau led to a higher level of tau oligomerization in SH-SY5Y neuroblastoma cells than wild type 0N4R, as determined by several orthogonal assays. Interestingly, the presence of GSK3β also enhanced tau release. Further, we demonstrated that cells endocytosed more monomeric tau protein when pre-phosphorylated by GSK3β. Using an extracellular vesicle (EVs)-assisted tau neuronal delivery system, we show that exosomal GSK3β-phosphorylated tau, when added to differentiated SH-SY5Y cells, induced more efficient tau transfer, showing much higher total tau levels and increased tau aggregate formation as compared to wild type exosomal tau. The role of a primary tau phosphorylation site targeted by microtubule-affinity regulating kinases (MARKs), Ser262, was tested by pseudo-phosphorylation using site-directed mutagenesis to aspartate (S262D). S262D tau overexpression significantly enhanced tau release and intracellular tau accumulation, which were concurrent with the increase of pathological states of tau, as determined by immunodetection. Importantly, phosphorylation-induced tau accumulation was augmented by co-transfecting S262D tau with GSK3β, suggesting a possible interplay between Ser262 phosphorylation and GSK3β activity in tau pathology. Lastly, we found that pre-treatment of cells with amyloid-β (Aβ) further tau phosphorylation and accumulation when Ser262 pre-phosphorylation was present, suggesting that S262 may be a primary mediator of Aβ-induced tau toxicity. These findings provide a potential therapeutic target for treating tau-related disorders by targeting specific phospho-tau isoforms and further elucidate the GSK3β-mediated pathological seeding mechanisms.
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Hamano, Tadanori, Soichi Enomoto, Norimichi Shirafuji, Masamichi Ikawa, Osamu Yamamura, Shu-Hui Yen, and Yasunari Nakamoto. "Autophagy and Tau Protein." International Journal of Molecular Sciences 22, no. 14 (July 12, 2021): 7475. http://dx.doi.org/10.3390/ijms22147475.

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Neurofibrillary tangles, which consist of highly phosphorylated tau protein, and senile plaques (SPs) are pathological hallmarks of Alzheimer’s disease (AD). In swollen axons, many autophagic vacuoles are observed around SP in the AD brain. This suggests that autophagy function is disturbed in AD. We used a neuronal cellular model of tauopathy (M1C cells), which harbors wild type tau (4R0N), to assess the effects of the lysosomotrophic agent NH4Cl, and autophagy inhibitors chloroquine and 3 methyladenine (3MA). It was found that chloroquine, NH4Cl and 3MA markedly increased tau accumulation. Thus, autophagy lysosomal system disturbances disturbed the degradation mechanisms of tau protein. Other studies also revealed that tau protein, including aggregated tau, is degraded via the autophagy lysosome system. Phosphorylated and C terminal truncated tau were also reported to disturb autophagy function. As a therapeutic strategy, autophagy upregulation was suggested. Thus far, as autophagy modulators, rapamycin, mTOCR1 inhibitor and its analogues, lithium, metformin, clonidine, curcumin, nicotinamide, bexaroten, and torehalose have been proposed. As a therapeutic strategy, autophagic modulation may be the next target of AD therapeutics.
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URAKAMI, Katsuya, Koichi ISHIGURO, Takaomi C. SAIDO, Takeshi IWATSUBO, Nobuyuki OKAMURA, Nobuo ITO, Kazutomi KANEMARU, et al. "Discussions on phosphorylated tau and other biochemical markers." Psychogeriatrics 4, s1 (March 2004): S45—S50. http://dx.doi.org/10.1111/j.1479-8301.2003.00031.x.

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35

Ihara, Yasuo, Masato Hasegawa, Maho Morishima, and Koji Takio. "Paired helical filaments (PHF) and abnormally phosphorylated tau." Neuroscience Research Supplements 16 (January 1991): VIII. http://dx.doi.org/10.1016/0921-8696(91)90616-u.

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36

Tanaka, Toshihisa, Khalid Iqbal, Ekkhart Trenkner, Dong Jie Liu, and Inge Grundke-Iqbal. "Abnormally phosphorylated tau in SY5Y human neuroblastoma cells." FEBS Letters 360, no. 1 (February 20, 1995): 5–9. http://dx.doi.org/10.1016/0014-5793(95)00061-d.

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37

Lin, Gaoping, Feiyan Zhu, Nicholas M. Kanaan, Rei Asano, Norimichi Shirafuji, Hirohito Sasaki, Tomohisa Yamaguchi, et al. "Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein." International Journal of Molecular Sciences 22, no. 21 (November 8, 2021): 12063. http://dx.doi.org/10.3390/ijms222112063.

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The neuropathological hallmarks of Alzheimer’s disease (AD) are senile plaques (SPs), which are composed of amyloid β protein (Aβ), and neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau protein. As bio-metal imbalance may be involved in the formation of NFT and SPs, metal regulation may be a direction for AD treatment. Clioquinol (CQ) is a metal-protein attenuating compound with mild chelating effects for Zn2+ and Cu2+, and CQ can not only detach metals from SPs, but also decrease amyloid aggregation in the brain. Previous studies suggested that Cu2+ induces the hyperphosphorylation of tau. However, the effects of CQ on tau were not fully explored. To examine the effects of CQ on tau metabolism, we used a human neuroblastoma cell line, M1C cells, which express wild-type tau protein (4R0N) via tetracycline-off (TetOff) induction. In a morphological study and ATP assay, up to 10 μM CQ had no effect on cell viability; however, 100 μM CQ had cytotoxic effects. CQ decreased accumulation of Cu+ in the M1C cells (39.4% of the control), and both total and phosphorylated tau protein. It also decreased the activity of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) (37.3% and 60.7% levels of the control, respectively), which are tau kinases. Of note, activation of protein phosphatase 2A (PP2A), which is a tau phosphatase, was also observed after CQ treatment. Fractionation experiments demonstrated a reduction of oligomeric tau in the tris insoluble, sarkosyl soluble fraction by CQ treatment. CQ also decreased caspase-cleaved tau, which accelerated the aggregation of tau protein. CQ activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Although further studies are needed to elucidate the mechanisms responsible for the effects of CQ on tau, CQ may shed light on possible AD therapeutics.
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38

Kobayashi, Keiko, Yanchen Liu, Hiroshi Ichikawa, Shigekazu Takemura, and Yukiko Minamiyama. "Effects of Bisphenol A on Oxidative Stress in the Rat Brain." Antioxidants 9, no. 3 (March 16, 2020): 240. http://dx.doi.org/10.3390/antiox9030240.

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We investigated the effect of bisphenol A (BPA) on oxidative stress and tau-related proteins in adult rat brains. BPA (10 mg/L) was administered to rats for eight weeks through their drinking water. The reactive oxygen species (ROS) scavenging capacity for hydroxyl radicals in the plasma was reduced after two weeks. In the hippocampus, four and eight weeks of BPA increased the ratio of oxidized DJ-1/DJ-1 (PARK7). The ratio of phosphorylated-GSK3β/GSK3β and phosphorylated-AKT/AKT increased after one week of BPA treatment. The ratio of phosphorylated JNK/JNK and phosphorylated-ERK/ERK increased after eight weeks of BPA; the elevation could be related to tau phosphorylation. Protein phosphatase 2A (PP2A) in the hippocampus decreased after eight weeks of BPA treatment. At that time, SOD1 was significantly induced, but no changes in SOD2 expression were apparent in the hippocampus. Furthermore, the ratio of phosphorylated-tau (PHF-1, Ser396/ Ser404) to total tau level did not change. However, PHF-1 or other sites of tau could be phosphorylated after eight weeks in the hippocampi of rats. BPA induced systemic oxidative stress and could change ROS-induced signaling pathways in the brain. These results suggest that mitochondrial dysfunction possibly is not responsible for oxidative stress and neurodegeneration due to low doses of BPA.
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39

Blennow, Kaj, Eugeen Vanmechelen, and Harald Hampel. "CSF Total tau, Aβ42 and Phosphorylated tau Protein as Biomarkers for Alzheimer's Disease." Molecular Neurobiology 24, no. 1-3 (2001): 087–98. http://dx.doi.org/10.1385/mn:24:1-3:087.

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40

Herukka, Sanna-Kaisa, Corina Pennanen, Hilkka Soininen, and Tuula Pirttilä. "P2-140: Cerebrospinal fluid Aβ42, tau and phosphorylated tau correlate with hippocampal atrophy." Alzheimer's & Dementia 2 (July 2006): S274. http://dx.doi.org/10.1016/j.jalz.2006.05.978.

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41

Robb, Elysia L., Ya Hui Hung, Irene Volitakis, Robert Cherny, and Ashley I. Bush. "P3-313: Copper induces accumulation of tau and phosphorylated tau in lipid rafts." Alzheimer's & Dementia 2 (July 2006): S467. http://dx.doi.org/10.1016/j.jalz.2006.05.1583.

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42

Martínez-Maldonado, Alejandra, Miguel Ángel Ontiveros-Torres, Charles R. Harrington, José Francisco Montiel-Sosa, Raúl García-Tapia Prandiz, Patricia Bocanegra-López, Andrew Michael Sorsby-Vargas, et al. "Molecular Processing of Tau Protein in Progressive Supranuclear Palsy: Neuronal and Glial Degeneration." Journal of Alzheimer's Disease 79, no. 4 (February 16, 2021): 1517–31. http://dx.doi.org/10.3233/jad-201139.

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Background: Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP) are examples of neurodegenerative diseases, characterized by abnormal tau inclusions, that are called tauopathies. AD is characterized by highly insoluble paired helical filaments (PHFs) composed of tau with abnormal post-translational modifications. PSP is a neurodegenerative disease with pathological and clinical heterogeneity. There are six tau isoforms expressed in the adult human brain, with repeated microtubule-binding domains of three (3R) or four (4R) repeats. In AD, the 4R:3R ratio is 1:1. In PSP, the 4R isoform predominates. The lesions in PSP brains contain phosphorylated tau aggregates in both neurons and glial cells. Objective: Our objective was to evaluate and compare the processing of pathological tau in PSP and AD. Methods: Double and triple immunofluorescent labeling with antibodies to specific post-translational tau modifications (phosphorylation, truncation, and conformational changes) and thiazin red (TR) staining were carried out and analyzed by confocal microscopy. Results: Our results showed that PSP was characterized by phosphorylated tau in neurofibrillary tangles (NFTs) and glial cells. Tau truncated at either Glu391 or Asp421 was not observed. Extracellular NFTs (eNFTs) and glial cells in PSP exhibited a strong affinity for TR in the absence of intact or phosphorylated tau. Conclusion: Phosphorylated tau was as abundant in PSP as in AD. The development of eNFTs from both glial cells and neuronal bodies suggests that truncated tau species, different from those observed in AD, could be present in PSP. Additional studies on truncated tau within PSP lesions could improve our understanding of the pathological processing of tau and help identify a discriminatory biomarker for AD and PSP.
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43

Buée, Luc, Laëtitia Troquier, Sylvie Burnouf, Karim Belarbi, Anneke Van der Jeugd, Tariq Ahmed, Francisco Fernandez-Gomez, et al. "From tau phosphorylation to tau aggregation: what about neuronal death?" Biochemical Society Transactions 38, no. 4 (July 26, 2010): 967–72. http://dx.doi.org/10.1042/bst0380967.

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Tau pathology is characterized by intracellular aggregates of abnormally and hyperphosphorylated tau proteins. It is encountered in many neurodegenerative disorders, but also in aging. These neurodegenerative disorders are referred to as tauopathies. Comparative biochemistry of the tau aggregates shows that they differ in both tau isoform phosphorylation and content, which enables a molecular classification of tauopathies. In conditions of dementia, NFD (neurofibrillary degeneration) severity is correlated to cognitive impairment and is often considered as neuronal death. Using tau animal models, analysis of the kinetics of tau phosphorylation, aggregation and neuronal death in parallel to electrophysiological and behavioural parameters indicates a disconnection between cognition deficits and neuronal cell death. Tau phosphorylation and aggregation are early events followed by cognitive impairment. Neuronal death is not observed before the oldest ages. A sequence of events may be the formation of toxic phosphorylated tau species, their aggregation, the formation of neurofibrillary tangles (from pre-tangles to ghost tangles) and finally neuronal cell death. This sequence will last from 15 to 25 years and one can ask whether the aggregation of toxic phosphorylated tau species is a protection against cell death. Apoptosis takes 24 h, but NFD lasts for 24 years to finally kill the neuron or rather to protect it for more than 20 years. Altogether, these data suggest that NFD is a transient state before neuronal death and that therapeutic interventions are possible at that stage.
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44

Nakayama, Yui, Satoru Morimoto, Misao Yoneda, Shigeki Kuzuhara, and Yasumasa Kokubo. "Cerebrospinal Fluid Biomarkers for Kii Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex." Journal of Neurodegenerative Diseases 2013 (March 27, 2013): 1–4. http://dx.doi.org/10.1155/2013/679089.

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Objective. Amyotrophic lateral sclerosis/parkinsonism-dementia complex is classified as one of the tauopathies. Methods. The total tau, phosphorylated tau, and amyloid β42 levels were assayed in cerebrospinal fluid from patients with Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex (), Alzheimer’s disease (), Parkinson’s disease (), amyotrophic lateral sclerosis (), and controls () using specific enzyme-linked immunosorbent assay methods. Results. Total tau and phosphorylated tau did not increase and amyloid β42 was relatively reduced in Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex. Relatively reduced amyloid β42 might discriminate Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex from amyotrophic lateral sclerosis and Parkinson’s disease, and the ratios of phosphorylated-tau to amyloid β42 could discriminate Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex from Alzheimer’s disease. Conclusions. Cerebrospinal fluid analysis may be useful to differentiate amyotrophic lateral sclerosis/parkinsonism-dementia complex from Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease.
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45

JENKINS, Scott M., Marcus ZINNERMAN, Craig GARNER, and Gail V. W. JOHNSON. "Modulation of tau phosphorylation and intracellular localization by cellular stress." Biochemical Journal 345, no. 2 (January 10, 2000): 263–70. http://dx.doi.org/10.1042/bj3450263.

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Tau is a microtubule-associated protein that is functionally modulated by phosphorylation and hyperphosphorylated in several neurodegenerative diseases. Because phosphorylation regulates both normal and pathological tau functioning, it is of great interest to identify the signalling pathways and enzymes capable of modulating tau phosphorylation in vivo. The present study examined changes in tau phosphorylation and localization in response to osmotic stress, which activates the stress-activated protein kinases (SAPKs), a family of proline-directed protein kinases shown to phosphorylate tau in vitro and hypothesized to phosphorylate tau in Alzheimer's disease. Immunoblot analysis with phosphorylation-dependent antibodies revealed that osmotic stress increased tau phosphorylation at the non-Ser/Thr-Pro sites Ser-262/356, within the microtubule-binding domain, as well as Ser/Thr-Pro sites outside of tau's microtubule-binding domain. Although all SAPKs examined were activated by osmotic stress, none of the endogenous SAPKs mediated the increase in tau phosphorylation. However, when transfected into SH-SY5Y cells, SAPK3, but not the other SAPKs examined, phosphorylated tau in situ in response to activation by osmotic stress. Osmotic-stress-induced tau phosphorylation correlated with a decrease in the amount of tau associated with the cytoskeleton and an increase in the amount of soluble tau. This stress-induced alteration in tau localization was only partially due to phosphorylation at Ser-262/356 by a staurosporine-sensitive, non-proline-directed, protein kinase. Taken together, these results suggest that osmotic stress activates at least two tau-directed protein kinases, one proline-directed and one non-proline-directed, that SAPK3 can phosphorylate tau on Ser/Thr-Pro residues in situ, and that Ser-262/356 phosphorylation only partially regulates tau localization in the cell.
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46

Paudel, H. K., J. Lew, Z. Ali, and J. H. Wang. "Brain proline-directed protein kinase phosphorylates tau on sites that are abnormally phosphorylated in tau associated with Alzheimer's paired helical filaments." Journal of Biological Chemistry 268, no. 31 (November 1993): 23512–18. http://dx.doi.org/10.1016/s0021-9258(19)49492-1.

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47

Hanger, D. P., J. P. Brion, J. M. Gallo, N. J. Cairns, P. J. Luthert, and B. H. Anderton. "Tau in Alzheimer's disease and Down's syndrome is insoluble and abnormally phosphorylated." Biochemical Journal 275, no. 1 (April 1, 1991): 99–104. http://dx.doi.org/10.1042/bj2750099.

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Some investigators have described the presence in Alzheimer's disease brain extracts of several abnormal forms of the microtubule-associated protein tau, based on their unusual mobility in SDS/PAGE. It has been proposed that these abnormal forms of tau may be the result of aberrant tau phosphorylation. In this study we show that tau in extracts of Alzheimer's disease brain can be separated into two fractions based upon its solubility (100,000 g x 1 h supernatant) in non-denaturing conditions (100 mM-Mes, pH 6.5, 0.5 mM-MgCl2, 1 mM-EGTA and 1 M-NaCl). The tau isoforms with decreased mobility in SDS/PAGE are predominantly in an insoluble fraction, whereas the soluble tau is indistinguishable by its mobility in SDS/PAGE from tau in soluble extracts of control brain. Insoluble tau displaying abnormal mobility on SDS/PAGE was only found in Alzheimer and adult Down's syndrome brains and was absent from the brains of age-matched controls and from foetal and infant Down's syndrome brains. There was a good correlation between the presence of insoluble tau in brain extracts and the abundance of neurofibrillary tangles and senile neuritic plaques. The monoclonal antibody Tau. 1 stained insoluble tau on Western blots only after treatment of the nitrocellulose transfers with alkaline phosphatase, implying that this insoluble tau is in a particular state of phosphorylation. We conclude that, in Alzheimer's disease, a fraction of tau has a modified phosphorylation state and a decreased solubility; these modifications may precede formation of the neurofibrillary tangles characteristic of Alzheimer's disease and Down's syndrome in adults.
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48

Ali, Addison, Kristeen Pareja, and Tara Tracy. "Acetylation of Tau Induces Alzheimer's Disease-Associated Tau in Transgenic Mice." Innovation in Aging 5, Supplement_1 (December 1, 2021): 958. http://dx.doi.org/10.1093/geroni/igab046.3457.

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Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by neurofibrillary tangles (NFTs) and amyloid beta plaques. These NFTs are made up of aggregated tau proteins. Tau is involved in stabilizing microtubules and does not usually display aggregation. Acetylation of tau protein causes an increase in tau aggregation but its role in AD progression is still not well understood. I hypothesized that enhanced acetylated tau results in an increase in AD-like tau pathology. To test this, a murine prion promoter-tauKQ transgene was injected into the mouse fertilized oocyte. The tauKQ mutation alters lysine to glutamine to mimic acetylation of tau. Nontransgenic mice were used as controls. AT8 and GT-38 antibodies were used in immunohistochemistry (IHC) to target phosphorylated tau and AD-associated tau, respectively. GT-38 is conformation-dependent and requires 3R and 4R tau isoforms which makes it specific to AD. Through immunofluorescence, increased phosphorylated tau was observed in the hippocampus of the tauKQ mice compared to the nontransgenic mice. I focused on the dentate gyrus, CA1 region, and the mossy fibers of the CA3 region since they are involved in many memory processes. Through chromogenic IHC, the tauKQ mice exhibited more 3R+4R tau isoform pathology in the mossy fibers than the nontransgenic mice. This data suggests that an acetylation mimic is sufficient to stimulate an abundance of AD-related tau pathology in transgenic mice which is consistent with my hypothesis. The tauKQ mouse model can assist in understanding the role of tau acetylation and tau progression for AD.
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49

Formichi, P., L. Parnetti, E. Radi, G. Cevenini, M. T. Dotti, and A. Federico. "CSF levels of β-amyloid 1-42, tau and phosphorylated tau protein in CADASIL." European Journal of Neurology 15, no. 11 (November 2008): 1252–55. http://dx.doi.org/10.1111/j.1468-1331.2008.02277.x.

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50

Cowan, Catherine M., Torsten Bossing, Anton Page, David Shepherd, and Amritpal Mudher. "Soluble hyper-phosphorylated tau causes microtubule breakdown and functionally compromises normal tau in vivo." Acta Neuropathologica 120, no. 5 (July 9, 2010): 593–604. http://dx.doi.org/10.1007/s00401-010-0716-8.

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