SUPPLEMENTARY Informationin Format Provided by Iqbalet Al

SUPPLEMENTARY Informationin Format Provided by Iqbalet Al

SUPPLEMENTARY INFORMATIONIn format provided by Iqbalet al.

Associated with

Supplementary information S1 (box) | Additional major findings in tau research

1986Self-assembly of tau into filaments by dialysis from 6M urea is demonstrated1

1987Ubiquitination of tau in Alzheimer neurofibrillary tangles is reported2,3

1989Localization of tau in the somatodendritic compartment is shown by in situ hybridization in normal and ADbrains4

1992–1993Isolation of tau protein kinase I (GSK-3β) and hyperphosphorylation of tau by this kinase are described5–7

1994Glycation of tau is found in PHFs8,9

1995An overexpression transgenic mouse model displaying pretangle phenotype is reported10

1996Enzymatic dephosphorylation, especially with PP2A, is found to convert AD P-tau into a seemingly normal protein that promotesmicrotubule assembly11

1996Glycosylation of tau in PHFs is discovered12

1996Tau assembly into filaments is reported to be facilitated by polyanions13,14

1997AD P-tau is observed to bind MAP1 and MAP2 and depolymerize microtubules, but this interaction does not result in formation of filaments15

1998Combined activities of PDPKs and non-PDPKs are found to be involved in abnormal hyperphosphorylation of tau16

1999Generation of a transgenic mouse model with a neurodegenerative tauopathy phenotype and tau pathology is reported18

2000PP2A is identified as the major regulator of phosphorylation of tau18,19

2001Aβ is found to enhance tau pathology in transgenic mice expressing mutated tau20,21

2002Tau is found to be essential for Aβ-induced neurotoxicity22

2004The FTDP-17 tau mutations are found to make tau a more favourable substrate for abnormal hyperphosphorylation than normal protein23

2005Reports of cloning of inhibitors 1 (I1PP2A) and 2 (I2PP2A) of PP2A from the human brain, and regulation of PP2A activity towards hyperphosphorylated tau by these inhibitors24

2005Microtubule stabilizing compound is shown to offset loss of tau in a transgenic mouse model of tauopathy25

2006Tau is found to become a preferred substrate for hyperphosphorylation when it is dissociated from microtubules and/or when it contains the amino-terminal inserts26

2006Extracellular tau is found to be toxic to neuronal cells27

2007A paper clip model of the conformation of tau is proposed28

2007Involvement of protein kinases and phosphatases and phosphorylation sites in self-assembly of tau into PHFs and disruption of microtubules is established29

2008Accumulation of tau truncated at Glu391 and at Asp421 is shown to directly correlate with progression of AD30

2010Phosphorylation of tau at Thr212, Thr231 and Ser262 combined is found to cause neurodegeneration31

2010Sodium selenate is shown to rescue tau pathology and behavioural deficits by stabilizing PP2A tau complex in transgenic mice overexpressing mutated tau32

2014Expression of I2CTF is found to produce both AD-type and ALS-type pathology and clinical phenotypes in rats33

2014Truncation of tau by asparaginylendopeptidase is found to result in a toxic fragment34

2015Passive immunization targeting the amino-terminal domain of tau is shown to rescue tau pathology and cognitive impairment in a transgenic mouse model of AD and tauopathies35

Abbreviations: Aβ, amyloid-β; AD, Alzheimer disease; ALS, amyotrophic lateral sclerosis; FTDP-17, frontotemporal dementia with parkinsonism linked to chromosome 17; MAP, microtubule-associated protein; PDPKs, proline-directed protein kinases; PHFs, paired helical filaments; PP2A, protein phosphatase 2A; P-tau, hyperphosphorylated tau.


1.Montejo de Garcini, E., Serrano, L.,& Avila, J. Self assembly of microtubule associated protein tau into filaments resembling those found in Alzheimer disease. Biochem. Biophys. Res. Commun. 141, 790–796 (1986).

2.Mori, H., Kondo, J. & Ihara, Y. Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science. 235, 1641–1644 (1987).

3.Perry, G. et al. Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains. Proc. Natl Acad. Sci. USA 84, 3033–3036 (1987).

4.Kosik, K. S. et al. Tau in situ hybridization in normal and Alzheimer brain: localization in the somatodendritic compartment. Ann. Neurol. 26, 352–361 (1989).

5.Ishiguro, K. et al. Tau protein kinase I converts normal tau protein into A68-like component of paired helical filaments. J. Biol. Chem. 267, 10897–10901 (1992).

6.Ishiguro, K. et al. Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett. 325, 167–172 (1993).

7.Takashima, A. et al. Tau protein kinase I is essential for amyloid beta-protein-induced neurotoxicity. Proc. Natl Acad. Sci. USA 90, 7789–7793 (1993).

8.Ledesma, M. D. et al. Analysis of microtubule-associated protein tau glycation in paired helical filaments. J. Biol. Chem. 269, 21614–21619 (1994).

9.Smith, M. A. et al. Advanced Maillard reaction end products are associated with Alzheimer disease pathology. Proc. Natl Acad. Sci. USA 91, 5710–5714 (1994).

10.Gotz, J. et al. Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J. 14, 1304–1313 (1995).

11.Wang, J. Z., Grundke-Iqbal, I. & Iqbal, K. Restoration of biological activity of Alzheimer abnormally phosphorylated tau by dephosphorylation with protein phosphatase-2A, -2B and -1. Brain Res. Mol. Brain Res. 38, 200–208 (1996).

12.Wang, J. Z., Grundke-Iqbal, I. & Iqbal, K. Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer's disease. Nat. Med. 2, 871–875 (1996).

13.Goedert, M. et al. Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383, 550–553 (1996).

14.Perez, M. et al.Polymerization of tau into filaments in the presence of heparin: the minimal sequence required for tau-tau interaction.J. Neurochem.67, 1183–1190 (1996).

15.Alonso, A. D. et al. 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. Proc. Natl Acad. Sci. USA 94, 298–303 (1997).

16.Sengupta, A. et al. Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. Arch. Biochem. Biophys. 357, 299–309 (1998).

17.Ishihara, T. et al. Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 24, 751–762 (1999).

18.Bennecib, M. et al. Role of protein phosphatase-2A and -1 in the regulation of GSK-3, cdk5 and cdc2 and the phosphorylation of tau in rat forebrain. FEBS Lett. 485, 87–93 (2000).

19.Gong, C. X. et al.Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer's disease. J. Biol. Chem. 275, 5535–5544 (2000).

20.Gotz, J. et al. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293, 1491–1495 (2001).

21.Lewis, J. et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491 (2001).

22.Rapoport, M. et al. Tau is essential to beta-amyloid-induced neurotoxicity. Proc. Natl Acad. Sci. USA 99, 6364–6369 (2002).

23.Alonso, A. D. et al. Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J. Biol. Chem. 279, 34873–34881 (2004).

24.Tsujio, I. et al. Inhibitors of protein phosphatase-2A from human brain structures, immunocytological localization and activities towards dephosphorylation of the Alzheimer type hyperphosphorylated tau. FEBS Lett. 579, 363–372 (2005).

25.Zhang, B. et al. Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proc. Natl Acad. Sci. USA 102, 227–231 (2005).

26.Sengupta, A., Grundke-Iqbal, I. & Iqbal, K. Regulation of phosphorylation of tau by protein kinases in rat brain. Neurochem. Res. 31, 1473–1480 (2006).

27.Gomez-Ramos, A. et al. Extracellular tau is toxic to neuronal cells. FEBS Lett. 580, 4842–4850 (2006).

28.Mandelkow, E. et al. Structural principles of tau and the paired helical filaments of Alzheimer's disease. Brain Pathol. 17, 83–90 (2007).

29.Wang, J. Z., Grundke-Iqbal, I. & Iqbal, K. Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur. J. Neurosci. 25, 59–68 (2007).

30.Basurto-Islas, G. et al. Accumulation of aspartic acid421- and glutamic acid391-cleaved tau in neurofibrillary tangles correlates with progression in Alzheimer disease. J. Neuropathol. Exp. Neurol. 67, 470–483 (2008).

31.Alonso, A. D. et al. Phosphorylation of tau at Thr212, Thr231, and Ser262 combined causes neurodegeneration. J. Biol. Chem. 285, 30851–30860 (2010).

32.van Eersel, J. et al. Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models. Proc. Natl Acad. Sci. USA 107, 13888–13893 (2010).

33.Wang, X. et al. Alzheimer disease and amyotrophic lateral sclerosis: an etiopathogenic connection. Acta Neuropathol. 127, 243–256 (2014).

34.Zhang, Z. et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease. Nat. Med. 20, 1254–1262 (2014).

35.Dai, C. L. et al. Passive immunization targeting the N-terminal projection domain of tau decreases tau pathology and improves cognition in a transgenic mouse model of Alzheimer disease and tauopathies. J. Neural Transm. 122, 607–617 (2015).