The elusive tau molecular structures: can we translate the recent breakthroughs into new targets for intervention?

1.

Abraha A, Ghoshal N, Gamblin TC, Cryns V, Berry RW, Kuret J, Binder LI (2000) C-terminal inhibition of tau assembly in vitro and in Alzheimer’s disease. J Cell Sci 113(Pt 21):3737–3745PubMed

2.

Ait-Bouziad N, Lv G, Mahul-Mellier A-L, Xiao S, Zorludemir G, Eliezer D, Walz T, Lashuel HA (2017) Discovery and characterization of stable and toxic tau/phospholipid oligomeric complexes. Nat Commun 8:1678. https://doi.org/10.1038/s41467-017-01575-4 CrossRefPubMed

3.

Al-Hilaly YK, Pollack SJ, Rickard JE, Simpson M, Raulin A-C, Baddeley T, Schellenberger P, Storey JMD, Harrington CR, Wischik CM, Serpell LC (2018) Cysteine-independent inhibition of Alzheimer’s disease-like paired helical filament assembly by Leuco-Methylthioninium (LMT). J Mol Biol 430:4119–4131. https://doi.org/10.1016/j.jmb.2018.08.010 CrossRefPubMed

4.

Al-Hilaly YK, Pollack SJ, Vadukul DM, Citossi F, Rickard JE, Simpson M, Storey JMD, Harrington CR, Wischik CM, Serpell LC (2017) Alzheimer’s disease-like paired helical filament assembly from truncated tau protein is independent of disulfide crosslinking. J Mol Biol 429:3650–3665. https://doi.org/10.1016/j.jmb.2017.09.007 CrossRefPubMed

5.

Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K (2001) Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U A 98:6923–6928CrossRef

6.

Alonso AC, Grundke-Iqbal I, Iqbal K (1996) Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat Med 2:783–787CrossRef

7.

Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K (1994) Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci U A 91:5562–5566CrossRef

8.

Ambadipudi S, Biernat J, Riedel D, Mandelkow E, Zweckstetter M (2017) Liquid-liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein tau. Nat Commun 8:275. https://doi.org/10.1038/s41467-017-00480-0 CrossRefPubMed

9.

Ando K, Leroy K, Héraud C, Yilmaz Z, Authelet M, Suain V, De Decker R, Brion J-P (2011) Accelerated human mutant tau aggregation by knocking out murine tau in a transgenic mouse model. Am J Pathol 178:803–816. https://doi.org/10.1016/j.ajpath.2010.10.034 CrossRefPubMed

10.

Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde Y-A, Duff K, Davies P (2003) Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 86:582–590CrossRef

11.

Andreasson U, Kuhlmann J, Pannee J, Umek RM, Stoops E, Vanderstichele H, Matzen A, Vandijck M, Dauwe M, Leinenbach A, Rutz S, Portelius E, Zegers I, Zetterberg H, Blennow K (2018) Commutability of the certified reference materials for the standardization of β-amyloid 1-42 assay in human cerebrospinal fluid: lessons for tau and β-amyloid 1-40 measurements. Clin Chem Lab Med 56:2058–2066. https://doi.org/10.1515/cclm-2018-0147 CrossRefPubMed

12.

Andronesi OC, von Bergen M, Biernat J, Seidel K, Griesinger C, Mandelkow E, Baldus M (2008) Characterization of Alzheimer’s-like paired helical filaments from the core domain of tau protein using solid-state NMR spectroscopy. J Am Chem Soc 130:5922–5928. https://doi.org/10.1021/ja7100517 CrossRefPubMed

13.

Armstrong RA, Lantos PL, Cairns NJ (2008) What determines the molecular composition of abnormal protein aggregates in neurodegenerative disease? Neuropathology 28:351–365. https://doi.org/10.1111/j.1440-1789.2008.00916.x CrossRefPubMed

14.

Asadollahi K, Riazi G, Rabbani Chadegani A, Rafiee S (2018) DNA-binding mode transition of tau in the presence of zinc ions. J Biomol Struct Dyn 36:1925–1933. https://doi.org/10.1080/07391102.2017.1343684 CrossRefPubMed

15.

Barghorn S, Davies P, Mandelkow E (2004) Tau paired helical filaments from Alzheimer’s disease brain and assembled in vitro are based on beta-structure in the core domain. Biochemistry 43:1694–1703. https://doi.org/10.1021/bi0357006 CrossRefPubMed

16.

Barthélemy NR, Fenaille F, Hirtz C, Sergeant N, Schraen-Maschke S, Vialaret J, Buée L, Gabelle A, Junot C, Lehmann S, Becher F (2016) Tau protein quantification in human cerebrospinal fluid by targeted mass spectrometry at high sequence coverage provides insights into its primary structure heterogeneity. J Proteome Res 15:667–676. https://doi.org/10.1021/acs.jproteome.5b01001 CrossRefPubMed

17.

Benhelli-Mokrani H, Mansuroglu Z, Chauderlier A, Albaud B, Gentien D, Sommer S, Schirmer C, Laqueuvre L, Josse T, Buée L, Lefebvre B, Galas M-C, Souès S, Bonnefoy E (2018) Genome-wide identification of genic and intergenic neuronal DNA regions bound by tau protein under physiological and stress conditions. Nucleic Acids Res 46:11405–11422. https://doi.org/10.1093/nar/gky929 CrossRefPubMed

18.

Berriman J, Serpell LC, Oberg KA, Fink AL, Goedert M, Crowther RA (2003) Tau filaments from human brain and from in vitro assembly of recombinant protein show cross-beta structure. Proc Natl Acad Sci U S A 100:9034–9038. https://doi.org/10.1073/pnas.1530287100 CrossRefPubMed

19.

Bibow S, Mukrasch MD, Chinnathambi S, Biernat J, Griesinger C, Mandelkow E, Zweckstetter M (2011) The dynamic structure of filamentous tau. Angew Chem Int Ed Engl 50:11520–11524. https://doi.org/10.1002/anie.201105493 CrossRefPubMed

20.

Bourré G, Cantrelle F-X, Kamah A, Chambraud B, Landrieu I, Smet-Nocca C (2018) Direct crosstalk between O-GlcNAcylation and phosphorylation of tau protein investigated by NMR spectroscopy. Front Endocrinol 9:595. https://doi.org/10.3389/fendo.2018.00595 CrossRef

21.

Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16:271–278 discussion 278-84CrossRef

22.

Braak H, Braak E (1997) Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 18:351–357CrossRef

23.

Brion JP, Flament-Durand J, Dustin P (1986) Alzheimer’s disease and tau proteins. Lancet 2:1098 doi: S0140-6736(86)90495-2CrossRef

24.

Carmel G, Mager EM, Binder LI, Kuret J (1996) The structural basis of monoclonal antibody Alz50’s selectivity for Alzheimer’s disease pathology. J Biol Chem 271:32789–32795CrossRef

25.

Chhatwal JP, Schultz AP, Marshall GA, Boot B, Gomez-Isla T, Dumurgier J, LaPoint M, Scherzer C, Roe AD, Hyman BT, Sperling RA, Johnson KA (2016) Temporal T807 binding correlates with CSF tau and phospho-tau in normal elderly. Neurology 87:920–926. https://doi.org/10.1212/WNL.0000000000003050 CrossRefPubMed

26.

Chien DT, Szardenings AK, Bahri S, Walsh JC, Mu F, Xia C, Shankle WR, Lerner AJ, Su M-Y, Elizarov A, Kolb HC (2014) Early clinical PET imaging results with the novel PHF-tau radioligand [F18]-T808. J Alzheimers Dis JAD 38:171–184. https://doi.org/10.3233/JAD-130098 CrossRefPubMed

27.

Chukwu JE, Pedersen JT, Pedersen LØ, Volbracht C, Sigurdsson EM, Kong X-P (2018) Tau antibody structure reveals a molecular switch defining a pathological conformation of the tau protein. Sci Rep 8:6209. https://doi.org/10.1038/s41598-018-24276-4 CrossRefPubMed

28.

Craven KM, Kochen WR, Hernandez CM, Flinn JM (2018) Zinc exacerbates tau pathology in a tau mouse model. J Alzheimers Dis JAD 64:617–630. https://doi.org/10.3233/JAD-180151 CrossRefPubMed

29.

Daebel V, Chinnathambi S, Biernat J, Schwalbe M, Habenstein B, Loquet A, Akoury E, Tepper K, Müller H, Baldus M, Griesinger C, Zweckstetter M, Mandelkow E, Vijayan V, Lange A (2012) β-Sheet core of tau paired helical filaments revealed by solid-state NMR. J Am Chem Soc 134:13982–13989. https://doi.org/10.1021/ja305470p CrossRefPubMed

30.

Dagley A, LaPoint M, Huijbers W, Hedden T, McLaren DG, Chatwal JP, Papp KV, Amariglio RE, Blacker D, Rentz DM, Johnson KA, Sperling RA, Schultz AP (2017) Harvard aging brain study: dataset and accessibility. NeuroImage 144:255–258. https://doi.org/10.1016/j.neuroimage.2015.03.069 CrossRefPubMed

31.

Dai C-L, Tung YC, Liu F, Gong C-X, Iqbal K (2017) Tau passive immunization inhibits not only tau but also Aβ pathology. Alzheimers Res Ther 9:1. https://doi.org/10.1186/s13195-016-0227-5 CrossRefPubMed

32.

de Calignon A, Fox LM, Pitstick R, Carlson GA, Bacskai BJ, Spires-Jones TL, Hyman BT (2010) Caspase activation precedes and leads to tangles. Nature 464:1201–1204. https://doi.org/10.1038/nature08890 CrossRefPubMed

33.

de Calignon A, Polydoro M, Suárez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Carlson GA, Spires-Jones TL, Hyman BT (2012) Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73:685–697. https://doi.org/10.1016/j.neuron.2011.11.033 CrossRefPubMed

34.

De Vos A, Struyfs H, Jacobs D, Fransen E, Klewansky T, De Roeck E, Robberecht C, Van Broeckhoven C, Duyckaerts C, Engelborghs S, Vanmechelen E (2016) The cerebrospinal fluid Neurogranin/BACE1 ratio is a potential correlate of cognitive decline in Alzheimer’s disease. J Alzheimers Dis JAD 53:1523–1538. https://doi.org/10.3233/JAD-160227 CrossRefPubMed

35.

Despres C, Byrne C, Qi H, Cantrelle F-X, Huvent I, Chambraud B, Baulieu E-E, Jacquot Y, Landrieu I, Lippens G, Smet-Nocca C (2017) Identification of the tau phosphorylation pattern that drives its aggregation. Proc Natl Acad Sci U S A 114:9080–9085. https://doi.org/10.1073/pnas.1708448114 CrossRefPubMed

36.

Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, Nguyen M, Haditsch U, Raha D, Griffin C, Holsinger LJ, Arastu-Kapur S, Kaba S, Lee A, Ryder MI, Potempa B, Mydel P, Hellvard A, Adamowicz K, Hasturk H, Walker GD, Reynolds EC, Faull RLM, Curtis MA, Dragunow M, Potempa J (2019) Porphyromonas gingivalis in Alzheimer’s disease brains: evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv 5:eaau3333. https://doi.org/10.1126/sciadv.aau3333 CrossRefPubMed

37.

Dujardin S, Bégard S, Caillierez R, Lachaud C, Carrier S, Lieger S, Gonzalez JA, Deramecourt V, Déglon N, Maurage C-A, Frosch MP, Hyman BT, Colin M, Buée L (2018) Different tau species lead to heterogeneous tau pathology propagation and misfolding. Acta Neuropathol Commun 6:132. https://doi.org/10.1186/s40478-018-0637-7 CrossRefPubMed

38.

Eftekharzadeh B, Daigle JG, Kapinos LE, Coyne A, Schiantarelli J, Carlomagno Y, Cook C, Miller SJ, Dujardin S, Amaral AS, Grima JC, Bennett RE, Tepper K, DeTure M, Vanderburg CR, Corjuc BT, DeVos SL, Gonzalez JA, Chew J, Vidensky S, Gage FH, Mertens J, Troncoso J, Mandelkow E, Salvatella X, Lim RYH, Petrucelli L, Wegmann S, Rothstein JD, Hyman BT (2018) Tau protein disrupts nucleocytoplasmic transport in Alzheimer’s disease. Neuron 99:925–940.e7. https://doi.org/10.1016/j.neuron.2018.07.039 CrossRefPubMed

39.

Eschmann NA, Georgieva ER, Ganguly P, Borbat PP, Rappaport MD, Akdogan Y, Freed JH, Shea J-E, Han S (2017) Signature of an aggregation-prone conformation of tau. Sci Rep 7:44739. https://doi.org/10.1038/srep44739 CrossRefPubMed

40.

Falcon B, Zhang W, Murzin AG, Murshudov G, Garringer HJ, Vidal R, Crowther RA, Ghetti B, Scheres SHW, Goedert M (2018) Structures of filaments from Pick’s disease reveal a novel tau protein fold. Nature 561:137–140. https://doi.org/10.1038/s41586-018-0454-y CrossRefPubMed

41.

Falcon B, Zhang W, Schweighauser M, Murzin AG, Vidal R, Garringer HJ, Ghetti B, Scheres SHW, Goedert M (2018) Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold. Acta Neuropathol (Berl) 136:699–708. https://doi.org/10.1007/s00401-018-1914-z CrossRef

42.

Fichou Y, Lin Y, Rauch JN, Vigers M, Zeng Z, Srivastava M, Keller TJ, Freed JH, Kosik KS, Han S (2018) Cofactors are essential constituents of stable and seeding-active tau fibrils. Proc Natl Acad Sci. https://doi.org/10.1073/pnas.1810058115

43.

Fichou Y, Vigers M, Goring AK, Eschmann NA, Han S (2018) Heparin-induced tau filaments are structurally heterogeneous and differ from Alzheimer’s disease filaments. Chem Commun 54:4573–4576. https://doi.org/10.1039/C8CC01355A CrossRef

44.

Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M, Scheres SHW (2017) Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547:185–190. https://doi.org/10.1038/nature23002 CrossRefPubMed

45.

Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL, Lu M, Fu Y, Garcia-Sierra F, LaPointe N, Miller R, Berry RW, Binder LI, Cryns VL (2003) Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc Natl Acad Sci U S A 100:10032–10037. https://doi.org/10.1073/pnas.1630428100 CrossRefPubMed

46.

Gandhi NS, Landrieu I, Byrne C, Kukic P, Amniai L, Cantrelle F-X, Wieruszeski J-M, Mancera RL, Jacquot Y, Lippens G (2015) A phosphorylation-induced turn defines the Alzheimer’s disease AT8 antibody epitope on the tau protein. Angew Chem Int Ed Engl 54:6819–6823. https://doi.org/10.1002/anie.201501898 CrossRefPubMed

47.

Garnier C, Devred F, Byrne D, Puppo R, Roman AY, Malesinski S, Golovin AV, Lebrun R, Ninkina NN, Tsvetkov PO (2017) Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates. Sci Rep 7:6812. https://doi.org/10.1038/s41598-017-07215-7 CrossRefPubMed

48.

Gauthier-Kemper A, Suárez Alonso M, Sündermann F, Niewidok B, Fernandez M-P, Bakota L, Heinisch JJ, Brandt R (2018) Annexins A2 and A6 interact with the extreme N terminus of tau and thereby contribute to tau’s axonal localization. J Biol Chem 293:8065–8076. https://doi.org/10.1074/jbc.RA117.000490 CrossRefPubMed

49.

Gigant B, Landrieu I, Fauquant C, Barbier P, Huvent I, Wieruszeski J-M, Knossow M, Lippens G (2014) Mechanism of tau-promoted microtubule assembly as probed by NMR spectroscopy. J Am Chem Soc 136:12615–12623. https://doi.org/10.1021/ja504864m CrossRefPubMed

50.

Ginsberg SD, Galvin JE, Chiu TS, Lee VM, Masliah E, Trojanowski JQ (1998) RNA sequestration to pathological lesions of neurodegenerative diseases. Acta Neuropathol (Berl) 96:487–494CrossRef

51.

Goedert M, Jakes R, Spillantini MG, Hasegawa M, Smith MJ, Crowther RA (1996) Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383:550–553. https://doi.org/10.1038/383550a0 CrossRefPubMed

52.

Goedert M, Spillantini MG (2017) Propagation of tau aggregates. Mol Brain 10:18. https://doi.org/10.1186/s13041-017-0298-7 CrossRefPubMed

53.

Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (1989) Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3:519–526 doi: 0896-6273(89)90210-9CrossRef

54.

Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM (1986) Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 261:6084–6089PubMed

55.

Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U A 83:4913–4917CrossRef

56.

Hanger DP, Betts JC, Loviny TL, Blackstock WP, Anderton BH (1998) New phosphorylation sites identified in hyperphosphorylated tau (paired helical filament-tau) from Alzheimer’s disease brain using nanoelectrospray mass spectrometry. J Neurochem 71:2465–2476CrossRef

57.

Hanseeuw BJ, Betensky RA, Schultz AP, Papp KV, Mormino EC, Sepulcre J, Bark JS, Cosio DM, LaPoint M, Chhatwal JP, Rentz DM, Sperling RA, Johnson KA (2017) Fluorodeoxyglucose metabolism associated with tau-amyloid interaction predicts memory decline. Ann Neurol 81:583–596. https://doi.org/10.1002/ana.24910 CrossRefPubMed

58.

Hanseeuw BJ, Mormino BC, Becker A, Sepulcre J, Papp KV, Schultz AP, Jacobs HI, Cosio DM, Chhatwal JP, Sperling RA, Johnson K (2017) Longitudinal tau accumulation is associated with cognitive decline in normal elderly. Alzheimers Dement J Alzheimers Assoc 13:P134–P136 doi: 10.1016/j.jalz.2017.06.2556CrossRef

59.

Hansson O, Mormino EC (2018) Is longitudinal tau PET ready for use in Alzheimer’s disease clinical trials? Brain J Neurol 141:1241–1244. https://doi.org/10.1093/brain/awy065 CrossRef

60.

Harrington CR, Mukaetova-Ladinska EB, Hills R, Edwards PC, Montejo de Garcini E, Novak M, Wischik CM (1991) Measurement of distinct immunochemical presentations of tau protein in Alzheimer disease. Proc Natl Acad Sci U S A 88:5842–5846CrossRef

61.

Harrison TM, La Joie R, Maass A, Baker SL, Swinnerton K, Fenton L, Mellinger TJ, Edwards L, Pham J, Miller BL, Rabinovici GD, Jagust WJ (2019) Longitudinal tau accumulation and atrophy in aging and alzheimer disease. Ann Neurol 85:229–240. https://doi.org/10.1002/ana.25406 CrossRefPubMed

62.

Hasegawa H, Holm L (2009) Advances and pitfalls of protein structural alignment. Curr Opin Struct Biol 19:341–348. https://doi.org/10.1016/j.sbi.2009.04.003 CrossRefPubMed

63.

Himmler A, Drechsel D, Kirschner MW, Martin DW Jr (1989) Tau consists of a set of proteins with repeated C-terminal microtubule-binding domains and variable N-terminal domains. Mol Cell Biol 9:1381–1388CrossRef

64.

Hu J-Y, Zhang D-L, Liu X-L, Li X-S, Cheng X-Q, Chen J, Du H-N, Liang Y (2017) Pathological concentration of zinc dramatically accelerates abnormal aggregation of full-length human tau and thereby significantly increases tau toxicity in neuronal cells. Biochim Biophys Acta Mol basis Dis 1863:414–427. https://doi.org/10.1016/j.bbadis.2016.11.022 CrossRefPubMed

65.

Huang Y, Wu Z, Cao Y, Lang M, Lu B, Zhou B (2014) Zinc binding directly regulates tau toxicity independent of tau hyperphosphorylation. Cell Rep 8:831–842. https://doi.org/10.1016/j.celrep.2014.06.047 CrossRefPubMed

66.

Huvent I, Kamah A, Cantrelle F-X, Barois N, Slomianny C, Smet-Nocca C, Landrieu I, Lippens G (2014) A functional fragment of tau forms fibers without the need for an intermolecular cysteine bridge. Biochem Biophys Res Commun 445:299–303. https://doi.org/10.1016/j.bbrc.2014.01.161 CrossRefPubMed

67.

Iqbal K, Alonso AC, Gong CX, Khatoon S, Singh TJ, Grundke-Iqbal I (1994) Mechanism of neurofibrillary degeneration in Alzheimer’s disease. Mol Neurobiol 9:119–123CrossRef

68.

Jack CR, Wiste HJ, Schwarz CG, Lowe VJ, Senjem ML, Vemuri P, Weigand SD, Therneau TM, Knopman DS, Gunter JL, Jones DT, Graff-Radford J, Kantarci K, Roberts RO, Mielke MM, Machulda MM, Petersen RC (2018) Longitudinal tau PET in ageing and Alzheimer’s disease. Brain J Neurol 141:1517–1528. https://doi.org/10.1093/brain/awy059 CrossRef

69.

Jadvah S, Avila J, Schöll M, Kovacs GG, Kövari E, Skrabana R, Evans LD, Kontsekova E, Malawska B, de Silva R, Buée L, Zilka N (2019) A walk through tau therapeutic strategies. Acta Neuropathol Commun 7:22. https://doi.org/10.1186/s40478-019-0664-z

70.

Jakes R, Novak M, Davison M, Wischik CM (1991) Identification of 3- and 4-repeat tau isoforms within the PHF in Alzheimer’s disease. EMBO J 10:2725–2729CrossRef

71.

Jeganathan S, Hascher A, Chinnathambi S, Biernat J, Mandelkow EM, Mandelkow E (2008) Proline-directed pseudo-phosphorylation at AT8 and PHF1 epitopes induces a compaction of the paperclip folding of tau and generates a pathological (MC-1) conformation. J Biol Chem 283:32066–32076. https://doi.org/10.1074/jbc.M805300200 CrossRefPubMed

72.

Johnson KA, Schultz A, Betensky RA, Becker JA, Sepulcre J, Rentz D, Mormino E, Chhatwal J, Amariglio R, Papp K, Marshall G, Albers M, Mauro S, Pepin L, Alverio J, Judge K, Philiossaint M, Shoup T, Yokell D, Dickerson B, Gomez-Isla T, Hyman B, Vasdev N, Sperling R (2016) Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol 79:110–119. https://doi.org/10.1002/ana.24546 CrossRefPubMed

73.

Kadavath H, Hofele RV, Biernat J, Kumar S, Tepper K, Urlaub H, Mandelkow E, Zweckstetter M (2015) Tau stabilizes microtubules by binding at the interface between tubulin heterodimers. Proc Natl Acad Sci U S A 112:7501–7506. https://doi.org/10.1073/pnas.1504081112 CrossRefPubMed

74.

Karch CM, Jeng AT, Goate AM (2012) Extracellular tau levels are influenced by variability in tau that is associated with tauopathies. J Biol Chem 287:42751–42762. https://doi.org/10.1074/jbc.M112.380642 CrossRefPubMed

75.

Kaufman SK, Sanders DW, Thomas TL, Ruchinskas AJ, Vaquer-Alicea J, Sharma AM, Miller TM, Diamond MI (2016) Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo. Neuron 92:796–812. https://doi.org/10.1016/j.neuron.2016.09.055 CrossRefPubMed

76.

Kellogg EH, Hejab NMA, Poepsel S, Downing KH, DiMaio F, Nogales E (2018) Near-atomic model of microtubule-tau interactions. Science 360:1242–1246. https://doi.org/10.1126/science.aat1780 CrossRefPubMed

77.

Kepe V, Bordelon Y, Boxer A, Huang S-C, Liu J, Thiede FC, Mazziotta JC, Mendez MF, Donoghue N, Small GW, Barrio JR (2013) PET imaging of neuropathology in tauopathies: progressive supranuclear palsy. J Alzheimers Dis JAD 36:145–153. https://doi.org/10.3233/JAD-130032 CrossRefPubMed

78.

La Joie R, Bejanin A, Fagan AM, Ayakta N, Baker SL, Bourakova V, Boxer AL, Cha J, Karydas A, Jerome G, Maass A, Mensing A, Miller ZA, O’Neil JP, Pham J, Rosen HJ, Tsai R, Visani AV, Miller BL, Jagust WJ, Rabinovici GD (2018) Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample. Neurology 90:e282–e290. https://doi.org/10.1212/WNL.0000000000004860 CrossRefPubMed

79.

Landau M, Sawaya MR, Faull KF, Laganowsky A, Jiang L, Sievers SA, Liu J, Barrio JR, Eisenberg D (2011) Towards a pharmacophore for amyloid. PLoS Biol 9:e1001080. https://doi.org/10.1371/journal.pbio.1001080 CrossRefPubMed

80.

Lee CM, Jacobs HIL, Marquié M, Becker JA, Andrea NV, Jin DS, Schultz AP, Frosch MP, Gómez-Isla T, Sperling RA, Johnson KA (2018) 18F-Flortaucipir binding in choroid plexus: related to race and Hippocampus signal. J Alzheimers Dis JAD 62:1691–1702. https://doi.org/10.3233/JAD-170840 CrossRefPubMed

81.

Lee G, Cowan N, Kirschner M (1988) The primary structure and heterogeneity of tau protein from mouse brain. Science 239:285–288CrossRef

82.

Li B, Chohan MO, Grundke-Iqbal I, Iqbal K (2007) Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau. Acta Neuropathol (Berl) 113:501–511. https://doi.org/10.1007/s00401-007-0207-8 CrossRef

83.

Li T, Braunstein KE, Zhang J, Lau A, Sibener L, Deeble C, Wong PC (2016) The neuritic plaque facilitates pathological conversion of tau in an Alzheimer’s disease mouse model. Nat Commun 7:12082. https://doi.org/10.1038/ncomms12082 CrossRefPubMed

84.

Liu C, Song X, Nisbet R, Götz J (2016) Co-immunoprecipitation with tau isoform-specific antibodies reveals distinct protein interactions and highlights a putative role for 2N tau in disease. J Biol Chem 291:8173–8188. https://doi.org/10.1074/jbc.M115.641902 CrossRefPubMed

85.

Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong C-X (2004) O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer’s disease. Proc Natl Acad Sci U S A 101:10804–10809. https://doi.org/10.1073/pnas.0400348101 CrossRefPubMed

86.

Liu F, Shi J, Tanimukai H, Gu J, Gu J, Grundke-Iqbal I, Iqbal K, Gong C-X (2009) Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer’s disease. Brain J Neurol 132:1820–1832. https://doi.org/10.1093/brain/awp099 CrossRef

87.

Luk C, Compta Y, Magdalinou N, Martí MJ, Hondhamuni G, Zetterberg H, Blennow K, Constantinescu R, Pijnenburg Y, Mollenhauer B, Trenkwalder C, Van Swieten J, Chiu WZ, Borroni B, Cámara A, Cheshire P, Williams DR, Lees AJ, de Silva R (2012) Development and assessment of sensitive immuno-PCR assays for the quantification of cerebrospinal fluid three- and four-repeat tau isoforms in tauopathies. J Neurochem 123:396–405. https://doi.org/10.1111/j.1471-4159.2012.07911.x CrossRefPubMed

88.

Mair W, Muntel J, Tepper K, Tang S, Biernat J, Seeley WW, Kosik KS, Mandelkow E, Steen H, Steen JA (2016) FLEXITau: quantifying post-translational modifications of tau protein in vitro and in human disease. Anal Chem 88:3704–3714. https://doi.org/10.1021/acs.analchem.5b04509 CrossRefPubMed

89.

Malia TJ, Teplyakov A, Ernst R, Wu S-J, Lacy ER, Liu X, Vandermeeren M, Mercken M, Luo J, Sweet RW, Gilliland GL (2016) Epitope mapping and structural basis for the recognition of phosphorylated tau by the anti-tau antibody AT8. Proteins 84:427–434. https://doi.org/10.1002/prot.24988 CrossRefPubMed

90.

Malki I, Cantrelle F-X, Sottejeau Y, Lippens G, Lambert J-C, Landrieu I (2017) Regulation of the interaction between the neuronal BIN1 isoform 1 and tau proteins - role of the SH3 domain. FEBS J 284:3218–3229. https://doi.org/10.1111/febs.14185 CrossRefPubMed

91.

Margittai M, Langen R (2004) Template-assisted filament growth by parallel stacking of tau. Proc Natl Acad Sci U S A 101:10278–10283. https://doi.org/10.1073/pnas.0401911101 CrossRefPubMed

92.

Marquié M, Normandin MD, Vanderburg CR, Costantino IM, Bien EA, Rycyna LG, Klunk WE, Mathis CA, Ikonomovic MD, Debnath ML, Vasdev N, Dickerson BC, Gomperts SN, Growdon JH, Johnson KA, Frosch MP, Hyman BT, Gómez-Isla T (2015) Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann Neurol 78:787–800. https://doi.org/10.1002/ana.24517 CrossRefPubMed

93.

Martinho M, Allegro D, Huvent I, Chabaud C, Etienne E, Kovacic H, Guigliarelli B, Peyrot V, Landrieu I, Belle V, Barbier P (2018) Two tau binding sites on tubulin revealed by thiol-disulfide exchanges. Sci Rep 8:13846. https://doi.org/10.1038/s41598-018-32096-9 CrossRefPubMed

94.

Mattsson N, Zetterberg H, Janelidze S, Insel PS, Andreasson U, Stomrud E, Palmqvist S, Baker D, Tan Hehir CA, Jeromin A, Hanlon D, Song L, Shaw LM, Trojanowski JQ, Weiner MW, Hansson O, Blennow K, Investigators ADNI (2016) Plasma tau in Alzheimer disease. Neurology 87:1827–1835. https://doi.org/10.1212/WNL.0000000000003246 CrossRefPubMed

95.

McMillan P, Korvatska E, Poorkaj P, Evstafjeva Z, Robinson L, Greenup L, Leverenz J, Schellenberg GD, D’Souza I (2008) Tau isoform regulation is region- and cell-specific in mouse brain. J Comp Neurol 511:788–803. https://doi.org/10.1002/cne.21867 CrossRefPubMed

96.

Medina M, Avila J (2014) The need for better AD animal models. Front Pharmacol 5:227. https://doi.org/10.3389/fphar.2014.00227 CrossRefPubMed

97.

Medina M, Hernández F, Avila J (2016) New features about tau function and dysfunction. Biomolecules 6. https://doi.org/10.3390/biom6020021

98.

Mena R, Edwards P, Pérez-Olvera O, Wischik CM (1995) Monitoring pathological assembly of tau and beta-amyloid proteins in Alzheimer’s disease. Acta Neuropathol (Berl) 89:50–56CrossRef

99.

Meredith JE, Sankaranarayanan S, Guss V, Lanzetti AJ, Berisha F, Neely RJ, Slemmon JR, Portelius E, Zetterberg H, Blennow K, Soares H, Ahlijanian M, Albright CF (2013) Characterization of novel CSF tau and ptau biomarkers for Alzheimer’s disease. PLoS One 8:e76523. https://doi.org/10.1371/journal.pone.0076523 CrossRefPubMed

100.

Meyer V, Holden MR, Weismiller HA, Eaton GR, Eaton SS, Margittai M (2016) Fracture and growth are competing forces determining the fate of conformers in tau fibril populations. J Biol Chem 291:12271–12281. https://doi.org/10.1074/jbc.M116.715557 CrossRefPubMed

101.

Mirbaha H, Chen D, Morazova OA, Ruff KM, Sharma AM, Liu X, Goodarzi M, Pappu RV, Colby DW, Mirzaei H, Joachimiak LA, Diamond MI (2018) Inert and seed-competent tau monomers suggest structural origins of aggregation. eLife 7:e36584. doi: https://doi.org/10.7554/eLife.36584

102.

Mo Z-Y, Zhu Y-Z, Zhu H-L, Fan J-B, Chen J, Liang Y (2009) Low micromolar zinc accelerates the fibrillization of human tau via bridging of Cys-291 and Cys-322. J Biol Chem 284:34648–34657. https://doi.org/10.1074/jbc.M109.058883 CrossRefPubMed

103.

Morishima-Kawashima M, Hasegawa M, Takio K, Suzuki M, Yoshida H, Watanabe A, Titani K, Ihara Y (1995) Hyperphosphorylation of tau in PHF. Neurobiol Aging 16:365–371 discussion 371-80CrossRef

104.

Morris DR, Levenson CW (2017) Neurotoxicity of zinc. Adv Neurobiol 18:303–312. https://doi.org/10.1007/978-3-319-60189-2_15 CrossRefPubMed

105.

Morris M, Knudsen GM, Maeda S, Trinidad JC, Ioanoviciu A, Burlingame AL, Mucke L (2015) Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat Neurosci 18:1183–1189. https://doi.org/10.1038/nn.4067nn.4067 CrossRefPubMed

106.

Moussaud S, Jones DR, Moussaud-Lamodière EL, Delenclos M, Ross OA, McLean PJ (2014) Alpha-synuclein and tau: teammates in neurodegeneration? Mol Neurodegener 9:43. https://doi.org/10.1186/1750-1326-9-43 CrossRefPubMed

107.

Mudher A, Brion J-P, Avila J, Medina M, Buée L (2017) EuroTau: towing scientists to tau without tautology. Acta Neuropathol Commun 5:90. https://doi.org/10.1186/s40478-017-0491-z CrossRefPubMed

108.

Nakamura A, Kaneko N, Villemagne VL, Kato T, Doecke J, Doré V, Fowler C, Li Q-X, Martins R, Rowe C, Tomita T, Matsuzaki K, Ishii K, Ishii K, Arahata Y, Iwamoto S, Ito K, Tanaka K, Masters CL, Yanagisawa K (2018) High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature 554:249–254. https://doi.org/10.1038/nature25456 CrossRefPubMed

109.

Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, Duyckaerts C, Frosch MP, Haroutunian V, Hof PR, Hulette CM, Hyman BT, Iwatsubo T, Jellinger KA, Jicha GA, Kövari E, Kukull WA, Leverenz JB, Love S, Mackenzie IR, Mann DM, Masliah E, McKee AC, Montine TJ, Morris JC, Schneider JA, Sonnen JA, Thal DR, Trojanowski JQ, Troncoso JC, Wisniewski T, Woltjer RL, Beach TG (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71:362–381. https://doi.org/10.1097/NEN.0b013e31825018f7 CrossRefPubMed

110.

Ng KP, Pascoal TA, Mathotaarachchi S, Therriault J, Kang MS, Shin M, Guiot M-C, Guo Q, Harada R, Comley RA, Massarweh G, Soucy J-P, Okamura N, Gauthier S, Rosa-Neto P (2017) Monoamine oxidase B inhibitor, selegiline, reduces 18F-THK5351 uptake in the human brain. Alzheimers Res Ther 9:25. https://doi.org/10.1186/s13195-017-0253-y CrossRefPubMed

111.

Nizynski B, Nieznanska H, Dec R, Boyko S, Dzwolak W, Nieznanski K (2018) Amyloidogenic cross-seeding of tau protein: transient emergence of structural variants of fibrils. PLoS One 13:e0201182. https://doi.org/10.1371/journal.pone.0201182 CrossRefPubMed

112.

Novak M, Kabat J, Wischik CM (1993) Molecular characterization of the minimal protease resistant tau unit of the Alzheimer’s disease paired helical filament. EMBO J 12:365–370CrossRef

113.

Novak P, Cehlar O, Skrabana R, Novak M (2018) Tau conformation as a target for disease-modifying therapy: the role of truncation. J Alzheimers Dis JAD 64:S535–S546. https://doi.org/10.3233/JAD-179942 CrossRefPubMed

114.

Ojo JO, Mouzon BC, Crawford F (2016) Repetitive head trauma, chronic traumatic encephalopathy and tau: challenges in translating from mice to men. Exp Neurol 275(Pt 3):389–404. https://doi.org/10.1016/j.expneurol.2015.06.003 CrossRefPubMed

115.

Oroz J, Chang BJ, Wysoczanski P, Lee C-T, Pérez-Lara Á, Chakraborty P, Hofele RV, Baker JD, Blair LJ, Biernat J, Urlaub H, Mandelkow E, Dickey CA, Zweckstetter M (2018) Structure and pro-toxic mechanism of the human Hsp90/PPIase/tau complex. Nat Commun 9:4532. https://doi.org/10.1038/s41467-018-06880-0 CrossRefPubMed

116.

Ossenkoppele R, Schonhaut DR, Schöll M, Lockhart SN, Ayakta N, Baker SL, O’Neil JP, Janabi M, Lazaris A, Cantwell A, Vogel J, Santos M, Miller ZA, Bettcher BM, Vossel KA, Kramer JH, Gorno-Tempini ML, Miller BL, Jagust WJ, Rabinovici GD (2016) Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease. Brain J Neurol 139:1551–1567. https://doi.org/10.1093/brain/aww027 CrossRef

117.

Ovod V, Ramsey KN, Mawuenyega KG, Bollinger JG, Hicks T, Schneider T, Sullivan M, Paumier K, Holtzman DM, Morris JC, Benzinger T, Fagan AM, Patterson BW, Bateman RJ (2017) Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement 13:841–849. https://doi.org/10.1016/j.jalz.2017.06.2266 CrossRefPubMed

118.

Pérez M, Medina M, Hernández F, Avila J (2018) Secretion of full-length tau or tau fragments in cell culture models. Propagation of tau in vivo and in vitro. Biomol Concepts 9:1–11. https://doi.org/10.1515/bmc-2018-0001 CrossRefPubMed

119.

Pérez-Ruiz E, Decrop D, Ven K, Tripodi L, Leirs K, Rosseels J, van de Wouwer M, Geukens N, De Vos A, Vanmechelen E, Winderickx J, Lammertyn J, Spasic D (2018) Digital ELISA for the quantification of attomolar concentrations of Alzheimer’s disease biomarker protein tau in biological samples. Anal Chim Acta 1015:74–81. https://doi.org/10.1016/j.aca.2018.02.011 CrossRefPubMed

120.

Pontecorvo MJ, Devous MD, Navitsky M, Lu M, Salloway S, Schaerf FW, Jennings D, Arora AK, McGeehan A, Lim NC, Xiong H, Joshi AD, Siderowf A, Mintun MA, 18F-AV-1451-A05 investigators (2017) Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition. Brain J Neurol 140:748–763. https://doi.org/10.1093/brain/aww334 CrossRef

121.

Poorkaj P, Kas A, D’Souza I, Zhou Y, Pham Q, Stone M, Olson MV, Schellenberg GD (2001) A genomic sequence analysis of the mouse and human microtubule-associated protein tau. Mamm Genome 12:700–712CrossRef

122.

Qi H, Cantrelle F-X, Benhelli-Mokrani H, Smet-Nocca C, Buée L, Lippens G, Bonnefoy E, Galas M-C, Landrieu I (2015) Nuclear magnetic resonance spectroscopy characterization of interaction of tau with DNA and its regulation by phosphorylation. Biochemistry 54:1525–1533. https://doi.org/10.1021/bi5014613 CrossRefPubMed

123.

Qi H, Prabakaran S, Cantrelle F-X, Chambraud B, Gunawardena J, Lippens G, Landrieu I (2016) Characterization of neuronal tau protein as a target of extracellular signal-regulated kinase. J Biol Chem 291:7742–7753. https://doi.org/10.1074/jbc.M115.700914 CrossRefPubMed

124.

Rábano A, Cuadros R, Calero M, Hernández F, Avila J (2013) Specific profile of tau isoforms in argyrophylic grain disease. J Exp Neurosci 7:51–59. https://doi.org/10.4137/JEN.S12202 CrossRefPubMed

125.

Rodriguez JA, Ivanova MI, Sawaya MR, Cascio D, Reyes FE, Shi D, Sangwan S, Guenther EL, Johnson LM, Zhang M, Jiang L, Arbing MA, Nannenga BL, Hattne J, Whitelegge J, Brewster AS, Messerschmidt M, Boutet S, Sauter NK, Gonen T, Eisenberg DS (2015) Structure of the toxic core of α-synuclein from invisible crystals. Nature 525:486–490. https://doi.org/10.1038/nature15368 CrossRefPubMed

126.

Rodríguez-Martín T, Cuchillo-Ibáñez I, Noble W, Nyenya F, Anderton BH, Hanger DP (2013) Tau phosphorylation affects its axonal transport and degradation. Neurobiol Aging 34:2146–2157. https://doi.org/10.1016/j.neurobiolaging.2013.03.015 CrossRefPubMed

127.

Roman AY, Devred F, Byrne D, La Rocca R, Ninkina NN, Peyrot V, Tsvetkov PO (2019) Zinc induces temperature-dependent reversible self-assembly of tau. J Mol Biol 431(4):687-695. doi: https://doi.org/10.1016/j.jmb.2018.12.008

128.

Rosseels J, Van den Brande J, Violet M, Jacobs D, Grognet P, Lopez J, Huvent I, Caldara M, Swinnen E, Papegaey A, Caillierez R, Buée-Scherrer V, Engelborghs S, Lippens G, Colin M, Buée L, Galas M-C, Vanmechelen E, Winderickx J (2015) Tau monoclonal antibody generation based on humanized yeast models: impact on tau oligomerization and diagnostics. J Biol Chem 290:4059–4074. https://doi.org/10.1074/jbc.M114.627919 CrossRefPubMed

129.

Sahara N, Maeda S, Murayama M, Suzuki T, Dohmae N, Yen S-H, Takashima A (2007) Assembly of two distinct dimers and higher-order oligomers from full-length tau. Eur J Neurosci 25:3020–3029. https://doi.org/10.1111/j.1460-9568.2007.05555.x CrossRefPubMed

130.

Sato C, Barthélemy NR, Mawuenyega KG, Patterson BW, Gordon BA, Jockel-Balsarotti J, Sullivan M, Crisp MJ, Kasten T, Kirmess KM, Kanaan NM, Yarasheski KE, Baker-Nigh A, Benzinger TLS, Miller TM, Karch CM, Bateman RJ (2018) Tau kinetics in neurons and the human central nervous system. Neuron 97:1284–1298.e7. https://doi.org/10.1016/j.neuron.2018.02.015 CrossRefPubMed

131.

Sawaya MR, Sambashivan S, Nelson R, Ivanova MI, Sievers SA, Apostol MI, Thompson MJ, Balbirnie M, Wiltzius JJW, McFarlane HT, Madsen AØ, Riekel C, Eisenberg D (2007) Atomic structures of amyloid cross-beta spines reveal varied steric zippers. Nature 447:453–457. https://doi.org/10.1038/nature05695 CrossRefPubMed

132.

Sayas CL, Medina M, Cuadros R, Ollá I, García E, Pérez M, Ferrer I, Hernández F, Avila J (2019) Role of tau N-terminal motif in the secretion of human tau by end binding proteins. PLoS One 14:e0210864. https://doi.org/10.1371/journal.pone.0210864 CrossRefPubMed

133.

Schneider A, Biernat J, von Bergen M, Mandelkow E, Mandelkow EM (1999) Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry 38:3549–3558CrossRef

134.

Schöll M, Maass A, Mattsson N, Ashton NJ, Blennow K, Zetterberg H, Jagust W (2018) Biomarkers for tau pathology. Mol Cell Neurosci. https://doi.org/10.1016/j.mcn.2018.12.001

135.

Seidler PM, Boyer DR, Rodriguez JA, Sawaya MR, Cascio D, Murray K, Gonen T, Eisenberg DS (2018) Structure-based inhibitors of tau aggregation. Nat Chem 10:170–176. https://doi.org/10.1038/nchem.2889 CrossRefPubMed

136.

Shih HH, Tu C, Cao W, Klein A, Ramsey R, Fennell BJ, Lambert M, Ní Shúilleabháin D, Autin B, Kouranova E, Laxmanan S, Braithwaite S, Wu L, Ait-Zahra M, Milici AJ, Dumin JA, LaVallie ER, Arai M, Corcoran C, Paulsen JE, Gill D, Cunningham O, Bard J, Mosyak L, Finlay WJJ (2012) An ultra-specific avian antibody to phosphorylated tau protein reveals a unique mechanism for phosphoepitope recognition. J Biol Chem 287:44425–44434. https://doi.org/10.1074/jbc.M112.415935 CrossRefPubMed

137.

Shimada H, Shinotoh H, Sahara N, Hirano S, Furukawa S, Takahata K, Ito H (2015) Diagnostic utility and clinical significance of tau PET imaging with [11C] PBB3 in diverse tauopathies. 9th Hum Amyloid Imaging Conf 2015 Miami, FL, USA

138.

Siddiqua A, Luo Y, Meyer V, Swanson MA, Yu X, Wei G, Zheng J, Eaton GR, Ma B, Nussinov R, Eaton SS, Margittai M (2012) Conformational basis for asymmetric seeding barrier in filaments of three- and four-repeat tau. J Am Chem Soc 134:10271–10278. https://doi.org/10.1021/ja303498q CrossRefPubMed

139.

Skrabana R, Kontsek P, Mederlyova A, Iqbal K, Novak M (2004) Folding of Alzheimer’s core PHF subunit revealed by monoclonal antibody 423. FEBS Lett 568:178–182. https://doi.org/10.1016/j.febslet.2004.04.098 CrossRefPubMed

140.

Smith R, Wibom M, Pawlik D, Englund E, Hansson O (2018) Correlation of in vivo [18F]Flortaucipir with postmortem Alzheimer disease tau pathology. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2018.3692

141.

Sotiropoulos I, Galas M-C, Silva JM, Skoulakis E, Wegmann S, Maina MB, Blum D, Sayas CL, Mandelkow E-M, Mandelkow E, Spillantini MG, Sousa N, Avila J, Medina M, Mudher A, Buee L (2017) Atypical, non-standard functions of the microtubule associated tau protein. Acta Neuropathol Commun 5:91. https://doi.org/10.1186/s40478-017-0489-6 CrossRefPubMed

142.

Spillantini MG, Crowther RA, Goedert M (1996) Comparison of the neurofibrillary pathology in Alzheimer’s disease and familial presenile dementia with tangles. Acta Neuropathol (Berl) 92:42–48CrossRef

143.

Spires-Jones TL, Kopeikina KJ, Koffie RM, de Calignon A, Hyman BT (2011) Are tangles as toxic as they look? J Mol Neurosci MN 45:438–444. https://doi.org/10.1007/s12031-011-9566-7 CrossRefPubMed

144.

Steen H, Mair W, Tang S, Steen JA (2017) Mapping the Tauopathy-specific modification landscape on tau. Alzheimers Dement 13:1229. https://doi.org/10.1016/j.jalz.2017.07.426 CrossRef

145.

Stefanoska K, Volkerling A, Bertz J, Poljak A, Ke YD, Ittner LM, Ittner A (2018) An N-terminal motif unique to primate tau enables differential protein-protein interactions. J Biol Chem 293:3710–3719. https://doi.org/10.1074/jbc.RA118.001784 CrossRefPubMed

146.

Stephens A, Seibyl J, Mueller A, Barret O, Berndt M, Madonia J, Kroth H, Bullich S, Pfeifer A, Muhs A, Tamagnan G, Marek K, Dinkelborg L (2018) CLINICAL UPDATE: [18F]PI-2620, a next generation tau PET agent evaluated in subjects with Alzheimer’s disease and progressive supranuclear palsy. Alzheimers Dement 14:P179. https://doi.org/10.1016/j.jalz.2018.06.2287 CrossRef

147.

Sutphen CL, Jasielec MS, Shah AR, Macy EM, Xiong C, Vlassenko AG, Benzinger TLS, Stoops EEJ, Vanderstichele HMJ, Brix B, Darby HD, Vandijck MLJ, Ladenson JH, Morris JC, Holtzman DM, Fagan AM (2015) Longitudinal cerebrospinal fluid biomarker changes in preclinical Alzheimer disease during middle age. JAMA Neurol 72:1029–1042. https://doi.org/10.1001/jamaneurol.2015.1285 CrossRefPubMed

148.

Taniguchi-Watanabe S, Arai T, Kametani F, Nonaka T, Masuda-Suzukake M, Tarutani A, Murayama S, Saito Y, Arima K, Yoshida M, Akiyama H, Robinson A, Mann DMA, Iwatsubo T, Hasegawa M (2016) Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau. Acta Neuropathol (Berl) 131:267–280. https://doi.org/10.1007/s00401-015-1503-3 CrossRef

149.

Tepper K, Biernat J, Kumar S, Wegmann S, Timm T, Hubschmann S, Redecke L, Mandelkow EM, Muller DJ, Mandelkow E (2014) Oligomer formation of tau protein hyperphosphorylated in cells. J Biol Chem 289:34389–34407. https://doi.org/10.1074/jbc.M114.611368 CrossRefPubMed

150.

Tsvetkov PO, Makarov AA, Malesinski S, Peyrot V, Devred F (2012) New insights into tau-microtubules interaction revealed by isothermal titration calorimetry. Biochimie 94:916–919. https://doi.org/10.1016/j.biochi.2011.09.011 CrossRefPubMed

151.

Tsvetkov PO, Roman AY, Baksheeva VE, Nazipova AA, Shevelyova MP, Vladimirov VI, Buyanova MF, Zinchenko DV, Zamyatnin AA, Devred F, Golovin AV, Permyakov SE, Zernii EY (2018) Functional status of neuronal calcium Sensor-1 is modulated by zinc binding. Front Mol Neurosci 11:459. https://doi.org/10.3389/fnmol.2018.00459 CrossRefPubMed

152.

Tuttle MD, Comellas G, Nieuwkoop AJ, Covell DJ, Berthold DA, Kloepper KD, Courtney JM, Kim JK, Barclay AM, Kendall A, Wan W, Stubbs G, Schwieters CD, Lee VMY, George JM, Rienstra CM (2016) Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein. Nat Struct Mol Biol 23:409–415. https://doi.org/10.1038/nsmb.3194 CrossRefPubMed

153.

Vandermeeren M, Borgers M, Van Kolen K, Theunis C, Vasconcelos B, Bottelbergs A, Wintmolders C, Daneels G, Willems R, Dockx K, Delbroek L, Marreiro A, Ver Donck L, Sousa C, Nanjunda R, Lacy E, Van De Casteele T, Van Dam D, De Deyn PP, Kemp JA, Malia TJ, Mercken MH (2018) Anti-tau monoclonal antibodies derived from soluble and filamentous tau show diverse functional properties in vitro and in vivo. J Alzheimers Dis JAD 65:265–281. https://doi.org/10.3233/JAD-180404 CrossRefPubMed

154.

Vanhelmont T, Vandebroek T, De Vos A, Terwel D, Lemaire K, Anandhakumar J, Franssens V, Swinnen E, Van Leuven F, Winderickx J (2010) Serine-409 phosphorylation and oxidative damage define aggregation of human protein tau in yeast. FEMS Yeast Res 10:992–1005. https://doi.org/10.1111/j.1567-1364.2010.00662.x CrossRefPubMed

155.

Vermeiren C, Motte P, Viot D, Mairet-Coello G, Courade J-P, Citron M, Mercier J, Hannestad J, Gillard M (2018) The tau positron-emission tomography tracer AV-1451 binds with similar affinities to tau fibrils and monoamine oxidases. Mov Disord Off J Mov Disord Soc 33:273–281. https://doi.org/10.1002/mds.27271 CrossRef

156.

von Bergen M, Barghorn S, Jeganathan S, Mandelkow EM, Mandelkow E (2006) Spectroscopic approaches to the conformation of tau protein in solution and in paired helical filaments. Neurodegener Dis 3:197–206. https://doi.org/10.1159/000095257 CrossRef

157.

von Bergen M, Friedhoff P, Biernat J, Heberle J, Mandelkow EM, Mandelkow E (2000) Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306) VQIVYK (311)) forming beta structure. Proc Natl Acad Sci U A 97:5129–5134 doi: 97/10/5129CrossRef

158.

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

159.

Wasmer C, Lange A, Van Melckebeke H, Siemer AB, Riek R, Meier BH (2008) Amyloid fibrils of the HET-s (218-289) prion form a beta solenoid with a triangular hydrophobic core. Science 319:1523–1526. https://doi.org/10.1126/science.1151839 CrossRefPubMed

160.

Watt NT, Whitehouse IJ, Hooper NM (2010) The role of zinc in Alzheimer’s disease. Int J Alzheimers Dis 2011:971021. https://doi.org/10.4061/2011/971021 CrossRefPubMed

161.

Wegmann S, Eftekharzadeh B, Tepper K, Zoltowska KM, Bennett RE, Dujardin S, Laskowski PR, MacKenzie D, Kamath T, Commins C, Vanderburg C, Roe AD, Fan Z, Molliex AM, Hernandez-Vega A, Muller D, Hyman AA, Mandelkow E, Taylor JP, Hyman BT (2018) Tau protein liquid-liquid phase separation can initiate tau aggregation. EMBO J 37. https://doi.org/10.15252/embj.201798049

162.

Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW (1975) A protein factor essential for microtubule assembly. Proc Natl Acad Sci U A 72:1858–1862CrossRef

163.

Weismiller HA, Murphy R, Wei G, Ma B, Nussinov R, Margittai M (2018) Structural disorder in four-repeat tau fibrils reveals a new mechanism for barriers to cross-seeding of tau isoforms. J Biol Chem 293(45):17336-17348. https://doi.org/10.1074/jbc.RA118.005316

164.

Wiedemann C, Bellstedt P, Görlach M (2013) CAPITO--a web server-based analysis and plotting tool for circular dichroism data. Bioinforma Oxf Engl 29:1750–1757. https://doi.org/10.1093/bioinformatics/btt278 CrossRef

165.

Wischik CM, Novak M, Edwards PC, Klug A, Tichelaar W, Crowther RA (1988) Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A 85:4884–4888CrossRef

166.

Wischik CM, Novak M, Thøgersen HC, Edwards PC, Runswick MJ, Jakes R, Walker JE, Milstein C, Roth M, Klug A (1988) Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A 85:4506–4510CrossRef

167.

Witman GB, Cleveland DW, Weingarten MD, Kirschner MW (1976) Tubulin requires tau for growth onto microtubule initiating sites. Proc Natl Acad Sci U S Am A 73:4070–4074CrossRef

168.

Yin H, Kuret J (2006) C-terminal truncation modulates both nucleation and extension phases of tau fibrillization. FEBS Lett 580:211–215. https://doi.org/10.1016/j.febslet.2005.11.077 CrossRefPubMed

169.

Zhang H, Zhu X, Pascual G, Wadia JS, Keogh E, Hoozemans JJ, Siregar B, Inganäs H, Stoop EJM, Goudsmit J, Apetri A, Koudstaal W, Wilson IA (2018) Structural basis for recognition of a unique epitope by a human anti-tau antibody. Structure 26:1626–1634. https://doi.org/10.1016/j.str.2018.08.012 CrossRefPubMed

170.

Zhang W, Falcon B, Murzin AG, Fan J, Crowther RA, Goedert M, Scheres SH (2019) Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases. eLife 8:e43584. https://doi.org/10.7554/eLife.43584 CrossRefPubMed

171.

Zhang Z, Song M, Liu X, Kang SS, Kwon I-S, Duong DM, Seyfried NT, Hu WT, Liu Z, Wang J-Z, Cheng L, Sun YE, Yu SP, Levey AI, Ye K (2014) Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat Med 20:1254–1262. https://doi.org/10.1038/nm.3700 CrossRefPubMed

172.

Zhong Q, Congdon EE, Nagaraja HN, Kuret J (2012) Tau isoform composition influences rate and extent of filament formation. J Biol Chem 287:20711–20719. https://doi.org/10.1074/jbc.M112.364067 CrossRefPubMed

173.

Zilka N, Kovacech B, Barath P, Kontsekova E, Novák M (2012) The self-perpetuating tau truncation circle. Biochem Soc Trans 40:681–686. https://doi.org/10.1042/BST20120015 CrossRefPubMed

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The elusive tau molecular structures: can we translate the recent breakthroughs into new targets for intervention?

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2019

The landscape of myeloid and astrocyte phenotypes in acute multiple sclerosis lesions

Synaptic localization of C9orf72 regulates post-synaptic glutamate receptor 1 levels

Aβ43 in human Alzheimer’s disease: effects of active Aβ42 immunization

Synapse alterations precede neuronal damage and storage pathology in a human cerebral organoid model of CLN3-juvenile neuronal ceroid lipofuscinosis

Response of the neurovascular unit to brain metastatic breast cancer cells

Clinical and neuropathological phenotype associated with the novel V189I mutation in the prion protein gene