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Open Access 01-04-2020 | Original Paper

Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy

Authors: Isidro Ferrer, Pol Andrés-Benito, Maria Victoria Zelaya, Maria Elena Erro Aguirre, Margarita Carmona, Karina Ausín, Mercedes Lachén-Montes, Joaquín Fernández-Irigoyen, Enrique Santamaría, José Antonio del Rio

Published in: Acta Neuropathologica | Issue 4/2020

Abstract

Globular glial tauopathy (GGT) is a progressive neurodegenerative disease involving the grey matter and white matter (WM) and characterized by neuronal deposition of hyper-phosphorylated, abnormally conformed, truncated, oligomeric 4Rtau in neurons and in glial cells forming typical globular astrocyte and oligodendrocyte inclusions (GAIs and GOIs, respectively) and coiled bodies. Present studies centre on four genetic GGT cases from two unrelated families bearing the P301T mutation in MAPT and one case of sporadic GGT (sGGT) and one case of GGT linked to MAPT K317M mutation, for comparative purposes. Clinical and neuropathological manifestations and biochemical profiles of phospho-tau are subjected to individual variations in patients carrying the same mutation, even in carriers of the same family, independently of the age of onset, gender, and duration of the disease. Immunohistochemistry, western blotting, transcriptomic, proteomics and phosphoproteomics, and intra-cerebral inoculation of brain homogenates to wild-type (WT) mice were the methods employed. In GGT cases linked to MAPT P301T mutation, astrocyte markers GFAP, ALDH1L1, YKL40 mRNA and protein, GJA1 mRNA, and AQ4 protein are significantly increased; glutamate transporter GLT1 (EAAT2) and glucose transporter (SLC2A1) decreased; mitochondrial pyruvate carrier 1 (MPC1) increased, and mitochondrial uncoupling protein 5 (UCP5) almost absent in GAIs in frontal cortex (FC). Expression of oligodendrocyte markers OLIG1 and OLIG2mRNA, and myelin-related genes MBP, PLP1, CNP, MAG, MAL, MOG, and MOBP are significantly decreased in WM; CNPase, PLP1, and MBP antibodies reveal reduction and disruption of myelinated fibres; and SMI31 antibodies mark axonal damage in the WM. Altered expression of AQ4, GLUC-t, and GLT-1 is also observed in sGGT and in GGT linked to MAPT K317M mutation. These alterations point to primary astrogliopathy and oligodendrogliopathy in GGT. In addition, GGT linked to MAPT P301T mutation proteotypes unveil a proteostatic imbalance due to widespread (phospho)proteomic dearrangement in the FC and WM, triggering a disruption of neuron projection morphogenesis and synaptic transmission. Identification of hyper-phosphorylation of variegated proteins calls into question the concept of phospho-tau-only alteration in the pathogenesis of GGT. Finally, unilateral inoculation of sarkosyl-insoluble fractions of GGT homogenates from GGT linked to MAPT P301T, sGGT, and GGT linked to MAPT K317M mutation in the hippocampus, corpus callosum, or caudate/putamen in wild-type mice produces seeding, and time- and region-dependent spreading of phosphorylated, non-oligomeric, and non-truncated 4Rtau and 3Rtau, without GAIs and GOIs but only of coiled bodies. These experiments prove that host tau strains are important in the modulation of cellular vulnerability and phenotypes of phospho-tau aggregates.

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Ahmed Z, Bigio EH, Budka H, Dickson DW, Ferrer I, Ghetti B et al (2013) Globular glial tauopathies (GGT): consensus recommendations. Acta Neuropathol 126:537–544PubMedPubMedCentral

Ahmed Z, Cooper J, Murray TK, Garn K, McNaughton E, Clarke H et al (2014) A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity. Acta Neuropathol 127:667–683PubMedPubMedCentral

Ahmed Z, Doherty KM, Silveira-Moriyama L, Bandopadhyay R, Lashley T, Mamais A et al (2011) Globular glial tauopathies (GGT) presenting with motor neuron disease or frontotemporal dementia: an emerging group of 4-repeat tauopathies. Acta Neuropathol 122:415–428PubMed

Andrés-Benito P, Gelpi E, Povedano M, Santpere G, Ferrer I (2018) Gene expression profile in frontal cortex in sporadic frontotemporal lobar degeneration-TDP. J Neuropathol Exp Neurol 77:608–627PubMed

Arai T, Ikeda K, Akiyama H, Nonaka T, Hasegawa M, Ishiguro K et al (2004) Identification of amino-terminally cleaved tau fragments that distinguish progressive supranuclear palsy from corticobasal degeneration. Ann Neurol 55:72–79PubMed

Audouard E, Houben S, Masaracchia C, Yilmaz Z, Suain V, Authelet M et al (2016) High-molecular weight paired helical filaments from Alzheimer brain induces seeding of wild-type mouse tau into argyrophilic 4R tau pathology in vivo. Am J Pathol 186:2709–2722PubMed

Bigio EH, Lipton AM, Yen SH, Hutton ML, Baker M, Nacharaju P et al (2001) Frontal lobe dementia with novel tauopathy: sporadic multiple system tauopathy with dementia. J Neuropathol Exp Neurol 60:328–341PubMed

Bleasel JM, Halliday GM, Kim WS (2016) Animal modeling an oligodendrogliopathy- multiple system atrophy. Acta Neuropathol Commun 4:12PubMedPubMedCentral

Boluda S, Iba M, Zhang B, Raible KM, Lee VM, Trojanowski JQ (2015) Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains. Acta Neuropathol 129:221–237PubMed

10.

Borrego-Ecija S, Morgado J, Palencia-Madrid L, Grau-Rivera O, Rene R, Hernandez I et al (2017) Frontotemporal dementia caused by the P301L mutation in the MAPT gene: clinicopathological features of 13 cases from the same geographical origin in Barcelona, Spain. Dement Geriatr Cogn Dis 4:213–221

11.

Burrell JR, Forrest S, Bak TH, Hodges JR, Halliday GM, Kril JJ (2016) Expanding the phenotypic associations of globular glial tau subtypes. Alzheimer’s Dement 4:6–13

12.

Butterfield DA (2019) Phosphoproteomics of Alzheimer disease brain: Insights into altered brain protein regulation of critical neuronal functions and their contributions to subsequent cognitive loss. Biochim Biophys Acta Mol Basis Dis 1865:2031–2039PubMed

13.

Chung DC, Carlomagno Y, Cook CN, Jansen-West K, Daughrity L, Lewis-Tuffin LJ et al (2019) Tau exhibits unique seeding properties in globular glial tauopathy. Acta Neuropathol Commun 7:36PubMedPubMedCentral

14.

Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J et al (2013) Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci USA 110:9535–9540PubMedPubMedCentral

15.

Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 111:909–913

16.

Clavaguera F, Hench J, Goedert M, Tolnay M (2015) Invited review: prion-like transmission and spreading of tau pathology. Neuropathol Appl Neurobiol 41:47–58PubMed

17.

Cong R, Das S, Ugrinova I, Kumar S, Mongerlard F, Wong J et al (2012) Interaction of nucleolin with ribosomal RNA genes and its role in RNA polymerase I transcription. Nucleic Acids Res 40:9441–9454PubMedPubMedCentral

18.

Costa C, Tortosa R, Rodríguez A, Ferrer I, Torres JM, Bassols A et al (2007) Aquaporin 1 and aquaporin 4 overexpression in bovine spongiform encephalopathy in a transgenic murine model and in cattle field cases. Brain Res 1175:96–106PubMed

19.

Cui Y, Masaki K, Yamasaki R, Imamura S, Suzuki SO, Hayashi S et al (2014) Extensive dysregulations of oligodendrocytic and astrocytic connexins are associated with disease progression in an amyotrophic lateral sclerosis mouse model. J Neuroinflamm 11:42

20.

Dabir DV, Robinson MB, Swanson E, Zhang B, Trojanowski JQ, Lee VM et al (2006) Impaired glutamate transport in a mouse model of tau pathology in astrocytes. J Neurosci 26:644–654PubMedPubMedCentral

21.

Dabir DV, Trojanowski JQ, Richter-Landsberg C, Lee VM, Forman MS (2004) Expression of the small heat-shock protein αB-crystallin in tauopathies with glial pathology. Am J Pathol 164:155–166PubMedPubMedCentral

22.

Dammer EB, Lee AK, Duong DM, Gearing M, Lah JJ, Levey AI et al (2015) Quantitative phosphoproteomics of Alzheimer's disease reveals cross-talk between kinases and small heat shock proteins. Proteomics 15:508–519PubMed

23.

DeLeo AM, Ikezu T (2018) Extracellular vesicle biology in Alzheimer's disease and related tauopathy. J Neuroimmune Pharmacol 13:292–308PubMed

24.

Di Domenico F, Sultana R, Barone E, Perluigi M, Cini C, Mancuso C et al (2011) Quantitative proteomics analysis of phosphorylated proteins in the hippocampus of Alzheimer's disease subjects. J Proteom 74:1091–1103

25.

Dujardin S, Bégard S, Caillierez R, Lachaud C, Carrier S, Lieger S et al (2018) Different tau species lead to heterogeneous tau pathology propagation and misfolding. Acta Neuropathol Commun 6:132PubMedPubMedCentral

26.

Dujardin S, Bégard S, Caillierez R, Lachaud C, Delattre L, Carrier S et al (2014) Ectosomes: a new mechanism for non-exosomal secretion of tau protein. PLoS ONE 9:e100760PubMedPubMedCentral

27.

Dujardin S, Lécolle K, Caillierez R, Bégard S, Zommer N, Lachaud C et al (2014) Neuron-to-neuron wild-type tau protein transfer through a trans-synaptic mechanism: relevance to sporadic tauopathies. Acta Neuropathol Commun 2:14PubMedPubMedCentral

28.

Erro ME, Zelaya MV, Mendioroz M, Larumbe R, Ortega-Cubero S, Lanciego JL et al (2019) Globular glial tauopathy caused by MAPT P301T mutation: clinical and neuropathological findings. J Neurol. https://doi.org/10.1007/s00415-019-09414-w CrossRefPubMed

29.

Ettle B, Schlachetzki JCM, Winkler J (2016) Oligodendroglia and myelin in neurodegenerative diseases: more than just bystanders? Mol Neurobiol 53:3046–3062PubMed

30.

Fellner L, Jellinger KA, Wenning GK, Stefanova N (2011) Glial dysfunction in the pathogenesis of α-synucleinopathies: emerging concepts. Acta Neuropathol 121:675–693PubMedPubMedCentral

31.

Ferrer I (2004) Stress kinases involved in tau phosphorylation in Alzheimer's disease, tauopathies and APP transgenic mice. Neurotoxicol Res 6:469–475

32.

Ferrer I (2012) Defining Alzheimer as a common age-related neurodegenerative process not inevitably leading to dementia. Prog Neurobiol 97:38–51PubMed

33.

Ferrer I (2017) Diversity of astroglial responses across human neurodegenerative disorders and brain aging. Brain Pathol 27:645–674PubMedPubMedCentral

34.

Ferrer I (2018) Astrogliopathy in tauopathies. Neuroglia 1:10

35.

Ferrer I (2018) Oligodendrogliopathy in neurodegenerative diseases with abnormal protein aggregates: the forgotten partner. Prog Neurobiol 169:24–54PubMed

36.

Ferrer I, Aguiló García M, Carmona M, Andrés-Benito P, Torrejón-Escribano B, Garcia-Esparcia P et al (2019) Involvement of oligodendrocytes in tau seeding and spreading in tauopathies. Front Aging Neurosci 11:112PubMedPubMedCentral

37.

Ferrer I, Aguiló García M, López González I, Diaz Lucena D, Roig Villalonga A, Carmona M et al (2018) Aging-related tau astrogliopathy (ARTAG): not only tau phosphorylation in astrocytes. Brain Pathol 28:965–985PubMedPubMedCentral

38.

Ferrer I, Hernandez I, Boada M, Llorente A, Rey MJ, Cardozo A et al (2003) Primary progressive aphasia as the initial manifestation of corticobasal degeneration and unusual tauopathies. Acta Neuropathol 106:419–435PubMed

39.

Ferrer I, Legati A, García-Monco JC, Gomez-Beldarrain M, Carmona M, Blanco R et al (2015) Familial behavioral variant frontotemporal dementia associated with astrocyte-predominant tauopathy. J Neuropathol Exp Neurol 74:370–379PubMed

40.

Ferrer I, López-González I, Carmona M, Arregui L, Dalfó E, Torrejón-Escribano B et al (2014) Glial and neuronal tau pathology in tauopathies: characterization of disease-specific phenotypes and tau pathology progression. J Neuropathol Exp Neurol 73:81–97PubMed

41.

Ferrer I, Zelaya MV, Aguiló García M, Carmona M, López-González I, Andrés-Benito P et al (2019) Relevance of host tau in tau seeding and spreading in tauopathies. Brain Pathol. https://doi.org/10.1111/bpa.12778. (epub ahead of print) CrossRefPubMedPubMedCentral

42.

Forrest SL, Halliday GM, McCann H, McGeachie AB, McGinley CV, Hodges JR et al (2019) Heritability in frontotemporal tauopathies. Alzheimer’s Dement 11:115–124

43.

Forrest SL, Kril J, Halliday G (2019) Cellular and regional vulnerability in frontotemporal tauopathies. Acta Neuropathol 138:705–727PubMed

44.

Forrest SL, Kril JJ, Stevens CH, Kwok JB, Hallupp M, Kim WS et al (2018) Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies. Brain 141:521–534PubMed

45.

Fu YJ, Nishihira Y, Kuroda S, Toyoshima Y, Ishihara T, Shinozaki M et al (2010) Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, Parkinsonism, and motor neuron disease: a distinct clinicopathological and biochemical disease entity. Acta Neuropathol 120:21–32PubMed

46.

Garcia-Esparcia P, Diaz-Lucena D, Ainciburu M, Torrejón-Escribano B, Carmona M, Llorens F et al (2018) Glutamate transprter GLT1 expression in Alzheimer’s disease and dementia with Lewy bodies. Front Aging Neurosci 10:122PubMedPubMedCentral

47.

Ghetti B, Oblak AL, Boeve BF, Johnson KA, Dickerson BC, Goedert M (2015) Invited review: frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging. Neuropathol Appl Neurobiol 41:24–46PubMedPubMedCentral

48.

Giaume C, Koulakoff A, Roux L, Holcman D, Rouach N (2010) Astroglial networks: a step further in neuroglial and gliovascular interactions. Nat Rev Neurosci 11:87–99PubMed

49.

Goedert M, Eisenberg DS, Crowther RA (2017) Propagation of tau aggregates and neurodegeneration. Ann Rev Neurosci 40:189–210PubMed

50.

Goedert M, Spillantini MG (2017) Propagation of tau aggregates. Mol Brain 10:18PubMedPubMedCentral

51.

Gomez-Ramos A, Diaz-Hernandez M, Rubio A, Diaz-Hernandez JI, Miras-Portugal MT, Avila J (2009) Characteristics and consequences of muscarinic receptor activation by tau protein. Eur Neuropsychopharmacol 19:708–717PubMed

52.

Goodenough DA, Goliger JA, Paul DL (1996) Connexins, connexons, and intercellular communication. Annu Rev Biochem 65:475–502PubMed

53.

Guix FX, Corbett GT, Cha DJ, Mustapic M, Liu W, Mengel D et al (2018) Detection of aggregation-competent tau in neuron-derived extracellular vesicles. Int J Mol Sci 19:663PubMedCentral

54.

Guo JL, Narasimhan S, Changolkar L, He Z, Stieber A, Zhang B et al (2016) Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice. J Exp Med 213:2635–2654PubMedPubMedCentral

55.

Hagiwara K, Hara H, Hanada K (2013) Species-barrier phenomenon in prion transmissibility from a viewpoint of protein science. J Biochem 153:139–145PubMed

56.

Hayashi S, Toyoshima Y, Hasegawa M, Umeda Y, Wakabayashi K, Tokiguchi S et al (2002) Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene mutation. Ann Neurol 51:525–530PubMed

57.

Hernandez-Ortega K, Garcia-Esparcia P, Gil L, Lucas JL, Ferrer I (2016) Altered machinery of protein synthesis in Alzheimer’s: from the nucleolus to the ribosome. Brain Pathol 26:593–605PubMed

58.

Higuchi M, Zhang B, Forman MS, Yoshiyama Y, Trojanowski JQ, Lee VM (2005) Axonal degeneration induced by targeted expression of mutant human tau in oligodendrocytes of transgenic mice that model glial tauopathies. J Neurosci 25:9434–9443PubMedPubMedCentral

59.

Holmes BB, De Vos SL, Kfoury N, Li M, Jacks R, Yanamandra K et al (2013) Heparan sulphate proteoglycans mediate internalization and propagation of specific proteopathic seeds. PNAS 110:E3138–3147PubMedPubMedCentral

60.

Hoshi A, Tsunoda A, Yamamoto T, Tada M, Kakita A, Ugawa Y (2018) Altered expression of glutamate transporter-1 and water channel protein aquaporin-4 in human temporal cortex with Alzheimer's disease. Neuropathol Appl Neurobiol 44:628–638PubMed

61.

Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM (2013) Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy. J Neurosci 33:1024–1037PubMedPubMedCentral

62.

Iseki E, Matsumura T, Marui W, Hino H, Odawara T, Sugiyama N et al (2001) Familial frontotemporal dementia and parkinsonism with a novel N296H mutation in exon 10 of the tau gene and a widespread tau accumulation in the glial cells. Acta Neuropathol 102:285–292PubMed

63.

Josephs KA, Katsuse O, Beccano-Kelly DA, Lin WL, Uitti RJ, Fujino Y et al (2006) Atypical progressive supranuclear palsy with corticospinal tract degeneration. J Neuropathol Exp Neurol 65:396–405PubMed

64.

Kampers T, Pangalos M, Geerts H, Wiech H, Mandelkow E (1999) Assembly of paired helical filaments from mouse tau: implications for the neurofibrillary pathology in transgenic mouse models of Alzheimer’s disease. FEBS Lett 451:39–44PubMed

65.

Koopmans F, van Nierop P, Andres-Alonso M, Byrnes A, Cijsouw T, Coba MP et al (2019) SynGO: an evidence-based, expert-curated knowledge base for the synapse. Neuron 103:217–234PubMedPubMedCentral

66.

Kotlyar M, Pastrello C, Pivetta F, Lo Sardo A, Cumbaa C, Li H et al (2015) In silico prediction of physical protein interactions and characterization of interactome orphans. Nat Methods 12:79–84PubMed

67.

Kovacs GG (2015) Tauopathies. In: Kovacs GG (ed) Neuropathology of neurodegenerative diseases: a practical guide. Cambridge University Press, Cambridge, pp 109–148

68.

Kovacs GG, Ferrer I, Grinberg LT, Alafuzoff I, Attems J, Budka H et al (2016) Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy. Acta Neuropathol 131:87–102PubMed

69.

Kovacs GG, Lee VM, Trojanowski JQ (2017) Protein astrogliopathies in human neurodegenerative diseases and aging. Brain Pathol 27:675–690PubMedPubMedCentral

70.

Kovacs GG, Majtenyi K, Spina S, Murrell JR, Gelpi E, Hoftberger R et al (2008) White matter tauopathy with globular glial inclusions: a distinct sporadic frontotemporal lobar degeneration. J Neuropathol Exp Neurol 67:963–975PubMed

71.

Kovacs GG, Yousef A, Kaindl S, Lee VM, Trojanowski JQ (2018) Connexin-43 and aquaporin-4 are markers of ageing-related tau astrogliopathy (ARTAG)-related astroglial response. Neuropathol Appl Neurobiol 44:491–505PubMed

72.

Lachén-Montes M, González-Morales A, Fernández-Irigoyen J, Santamaría E (2019) Determination of cerebrospinal fluid proteome variations by isobaric labeling coupled with strong cation-exchange chromatography and tandem mass spectrometry. Methods Mol Biol 2044:155–168PubMed

73.

Lachén-Montes M, González-Morales A, Iloro I, Elortza F, Ferrer I, Gveric D et al (2019) Unveiling the olfactory proteostatic disarrangement in Parkinson's disease by proteome-wide profiling. Neurobiol Aging 73:123–134PubMed

74.

Lachén-Montes M, González-Morales A, Schvartz D, Zelaya MV, Ausin K, Fernández-Irigoyen J et al (2019) The olfactory bulb proteotype differs across frontotemporal dementia spectrum. J Proteom 201:37–47

75.

Lachén-Montes M, González-Morales A, Zelaya MV, Pérez-Valderrama E, Ausín K, Ferrer I et al (2017) Olfactory bulb neuroproteomics reveals a chronological perturbation of survival routes and a disruption of prohibitin complex during Alzheimer's disease progression. Sci Rep 7:9115PubMedPubMedCentral

76.

Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Guerrero-Muñoz MJ, Kiritoshi T, Neugebauer V et al (2012) Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau. Sci Rep 2:700PubMedPubMedCentral

77.

Lassen PS, Thygesen C, Larsen MR, Kempf SJ (2017) Understanding Alzheimer's disease by global quantification of protein phosphorylation and sialylated N-linked glycosylation profiles: a chance for new biomarkers in neuroproteomics? J Proteom 161:11–25

78.

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

79.

Lewis J, Dickson DW (2016) Propagation of tau pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. Acta Neuropathol 131:27–48PubMed

80.

Lin WL, Lewis J, Yen SH, Hutton M, Dickson DW (2003) Filamentous tau oligodendrocytes and astrocytes of transgenic mice expressing the human tau isoform with the P301L mutation. Am J Pathol 162:213–218PubMedPubMedCentral

81.

Lin WL, Zehr C, Lewis J, Hutton M, Yen SH, Dickson DW (2005) Progressive white matter pathology in the spinal cord of transgenic mice expressing mutant (P301L) human tau. J Neurocytol 34:397–410PubMed

82.

Liu C, Götz J (2013) Profiling murine tau with 0N, 1N and 2N isoform-specific antibodies in brain and peripheral organs reveals distinct subcellular localization, with the 1N isoform being enriched in the nucleus. PLoS ONE 8:e84849PubMedPubMedCentral

83.

Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C et al (2012) Trans-synaptic spread of tau pathology in vivo. PLoS ONE 7:e31302PubMedPubMedCentral

84.

López-González I, Aso E, Carmona M, Armand-Ugon M, Blanco R, Naudí A et al (2015) Neuroinflammatory gene regulation, mitochondrial function, oxidative stress, and brain lipid modifications with disease progression in tau P301S transgenic mice as a model of frontotemporal lobar degeneration-tau. J Neuropathol Exp Neurol 74:975–999PubMed

85.

López-González I, Carmona M, Arregui L, Kovacs GG, Ferrer I (2014) αB-crystallin and HSP27 in glial cells in tauopathies. Neuropathology 34:517–526PubMed

86.

Maragakis NJ, Rothstein JD (2006) Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2:679–689PubMed

87.

Masliah E, Alford M, Mallory M, Rockenstein E, Moechars D, Van Leuven F (2000) Abnormal glutamate transport function in mutant amyloid precursor protein transgenic mice. Exp Neurol 163:381–387PubMed

88.

McMillan P, Korvatska E, Poorkaj P, Evstafjeva Z, Robinson L, Greenup L et al (2008) Tau isoform regulation is region and cell-specific in mouse brain. J Comp Neurol 511:788–803PubMedPubMedCentral

89.

Mei X, Ezan P, Giaume C, Koulakoff A (2010) Astroglial connexion immunoreactivity is specifically altered at β-amyloid plaques in β-amyloid precursor protein/presenilin1 mice. Neuroscience 171:92–105PubMed

90.

Nagy JI, Li W, Hertzberg EL, Marotta CA (1996) Elevated connexin43 immunoreactivity at sites of amyloid plaques in Alzheimer’s disease. Brain Res 717:173–178PubMed

91.

Nagy JI, Rash JE (2000) Connexins and gap junctions of astrocytes and oligodendrocytes in the CNS. Brain Res Brain Res Rev 32:29–44PubMed

92.

Narasimhan S, Guo JL, Changolkar L, Stieber A, McBride JD, Silva LV et al (2017) Pathological tau strains from human brains recapitulate the diversity of tauopathies in non-transgenic mouse brain. J Neurosci 37:11406–11423PubMedPubMedCentral

93.

Olofson HEK, Englund E (2019) A cortical microvascular structure in vascular dementia, Alzheimer's disease, frontotemporal lobar degeneration and nondemented controls: a sign of angiogenesis due to brain ischaemia? Neuropathol Appl Neurobiol 45:557–569

94.

Osborn LM, KamphuisW WadmanWJ, Hol EM (2016) Astrogliosis: an integral player in the pathogenesis of Alzheimer’s disease. Prog Neurobiol 144:121–141PubMed

95.

Oughtred R, Stark C, Breitkreutz BJ, Rust J, Boucher L, Chang C et al (2019) The BioGRID interaction database: 2019 update. Nucleic Acids Res 47:D529–D541PubMed

96.

Paxinos G, Franklin KBJ (2004) The mouse brain in stereotaxic coordinates. Elsevier, Academic, Amsterdam

97.

Pekny M, Pekna M, Messing A, Steinheauser C, Lee JM, Parpura V et al (2016) Astrocytes: a central element in neurological diseases. Acta Neuropathol 131:323–345PubMed

98.

Puig B, Viñals F, Ferrer I (2004) Active stress kinase p38 enhances and perpetuates abnormal tau phosphorylation and deposition in Pick's disease. Acta Neuropathol 107:185–189PubMed

99.

Radford RA, Morsch M, Rayner SL, Cole NJ, Pountney DL, Chung RS (2015) The established and emerging roles of astrocytes and microglia in amyotrophic lateral sclerosis and frontotemporal dementia. Front Cell Neurosci 9:414PubMedPubMedCentral

100.

Ren Y, Lin WL, Sanchez L, Ceballos C, Polydoro M, Spires-Jones TL et al (2014) Endogenous tau aggregates in oligodendrocytes of rTg4510 mice induced by human P301 L tau. J Alzheimers Dis 38:589–600PubMed

101.

Sattler R, Rothstein JD (2006) Regulation and dysregulation of glutamate transporters. Handb Exp Pharmacol 175:277–303

102.

Sayas CL, Medina M, Cuadros R, Ollá I, García E, Pérez M et al (2019) Role of tau N-terminal motif in the secretion of human tau by End Binding proteins. PLoS ONE 14:e0210864PubMedPubMedCentral

103.

Seifert G, Schilling K, Steinhauser C (2006) Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci 7:194–206PubMed

104.

Sharma A, Bruce KL, Chen B, Gyoneva S, Behrens SH, Bommarius AS et al (2016) Contributions of the prion protein sequence, strain, and environment to the species barrier. J Biol Chem 291:1277–1288PubMed

105.

Sharma K, Schmitt S, Bergner CG, Tyanova S, Kannaiyan N, Manrique-Hoyos N et al (2015) Cell type- and brain region-resolved mouse brain proteome. Nat Neurosci 18:1819–1831PubMedPubMedCentral

106.

Siman R, Lin YG, Malthankar-Phatak G, Dong Y (2013) A rapid gene delivery–based mouse model for early-stage Alzheimer’s disease-type tauopathy. J Neuropathol Exp Neurol 72:1062–1071PubMed

107.

Simpson JE, Ince PG, Lace G, Forster G, Shaw PJ, Matthews F et al (2010) Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain. Neurobiol Aging 31:578–590PubMed

108.

Spillantini MG, Goedert M (1998) Tau protein pathology in neurodegenerative diseases. Trends Neurosci 21:428–433PubMed

109.

Stancu IC, Vasconcelos B, Ris L, Wang P, Villers A, Peeraer E et al (2015) Templated misfolding of tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in tau transgenic mice. Acta Neuropathol 129:875–894PubMedPubMedCentral

110.

Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J et al (2019) STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 47:D607–D613PubMed

111.

Tacik P, DeTure M, Lin WL, Sánchez Contreras M, Wojtas A, Hinkle KM et al (2015) A novel tau mutation, p. K317N, causes globular glial tauopathy. Acta Neuropathol 130:199–214PubMedPubMedCentral

112.

Tacik P, Sanchez-Contreras M, DeTure M, Murray ME, Rademakers R, Ross OA et al (2017) Clinicopathologic heterogeneity in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) due to microtubule-associated protein tau (MAPT) p. P301L mutation, including a patient with globular glial tauopathy. Neuropathol Appl Neurobiol 43:200–214PubMedPubMedCentral

113.

Tagawa K, Homma H, Saito A, Fujita K, Chen X, Imoto S et al (2015) Comprehensive phosphoproteome analysis unravels the core signaling network that initiates the earliest synapse pathology in preclinical Alzheimer's disease brain. Hum Mol Genet 24:540–558PubMed

114.

Tamada H, Thuan NV, Reed P, Nelson D, Katoku-Kikyo N, Wudel J et al (2006) Chromatin decondensation and nuclear reprogramming by nucleoplasmin. Mol Cell Biol 26:1259–1271PubMedPubMedCentral

115.

Tan H, Wu Z, Wang H, Bai B, Li Y, Wang X et al (2015) Refined phosphopeptide enrichment by phosphate additive and the analysis of human brain phosphoproteome. Proteomics 15:500–507PubMed

116.

Tanaka H, Toyoshima Y, Kawakatsu S, Kobayashi R, Yokota O, Terada S et al (2019) Morphological characterisation of glial and neuronal tau pathology in globular glial tauopathy (types II and III). Neuropathol Appl Neurobiol. https://doi.org/10.1111/nan.12581. (epub ahead of print) CrossRefPubMed

117.

Taniguchi-Watanabe S, Arai T, Kametani F, Nonaka T, Masuda-Suzukake M, Tarutani A et al (2016) Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau. Acta Neuropathol 131:267–280PubMed

118.

Tardivel M, Begard S, Bousset L, Dujardin S, Coens A, Melki R et al (2016) Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies. Acta Neuropathol Commun 4:117PubMedPubMedCentral

119.

Thingholm TE, Jensen ON, Robinson PJ, Larsen MR (2008) SIMAC (sequential elution from IMAC), a phosphoproteomics strategy for the rapid separation of monophosphorylated from multiply phosphorylated peptides. Mol Cell Proteom 7:661–671

120.

Tyanova S, Temu T, Sinitcyn P, Carlson A, Hein MY, Geiger T et al (2016) The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat Methods 13:731–740PubMed

121.

Triplett JC, Swomley AM, Cai J, Klein JB, Butterfield DA (2016) Quantitative phosphoproteomic analyses of the inferior parietal lobule from three different pathological stages of Alzheimer's disease. J Alzheimers Dis 49:45–62PubMed

122.

Vaquer-Alicea J, Diamond MI (2019) Propagation of protein aggregation in neurodegenerative diseases. Annu Rev Biochem 88:785–810PubMed

123.

Verkhratsky A, Parpura V, Pekna M, Pekny M, Sofroniew M (2014) Glia in the pathogenesis of neurodegenerative diseases. Biochem Soc Trans 42:1291–1301PubMed

124.

Verkhratsky A, Zorec R, Parpura V (2017) Stratification of astrocytes in healthy and diseased brain. Brain Pathol 27:629–644PubMedPubMedCentral

125.

Verkhratsky A, Zorec R, Rodriguez JJ, Parpura V (2017) Neuroglia: functional paralysis and reactivity in Alzheimer's disease and other neurodegenerative pathologies. Adv Neurobiol 15:427–449PubMed

126.

Vis JC, Nicholson LF, Faull RL, EvansWH SNJ, Green CR (1998) Connexin expression in Huntington’s diseased human brain. Cell Biol Int 22:837–847PubMed

127.

Wang B, Han S (2018) Exosome-associated tau exacerbates brain functional impairments induced by traumatic brain injury in mice. Mol Cell Neurosci 88:158–166PubMed

128.

Wang Y, Balaji V, Kaniyappan S, Kruger L, Irsen S, Tepper K et al (2017) The release and trans-synaptic transmission of Tau via exosomes. Mol Neurodegener 12:5PubMedPubMedCentral

129.

Wenning GK, Stefanova N, Jellinger KA, Poewe W, Schlossmacher MG (2008) Multiple system atrophy: a primary oligodendrogliopathy. Ann Neurol 64:239–246PubMed

130.

Wu JW, Herman M, Liu L, Simoes S, Acker CM, Figueroa H et al (2013) Small misfolded Tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J Biol Chem 288:1856–1870PubMed

131.

Yamada K, Cirrito JR, Stewart FR, Jianq H, Finn MB, Holmes BB et al (2011) In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci 31:13110–13117PubMedPubMedCentral

132.

Yamanaka K, Komine O (2018) The multi-dimensional roles of astrocytes in ALS. Neurosci Res 126:31–38PubMed

133.

Yeung MS, Zdunek S, Bergmann O, Bernard S, Salehpour M, Alkass K et al (2014) Dynamics of oligodendrocyte generation and myelination in the human brain. Cell 159:766–774PubMed

134.

Zahid S, Oellerich M, Asif AR, Ahmed N (2012) Phosphoproteome profiling of substantia nigra and cortex regions of Alzheimer's disease patients. J Neurochem 121:954–963PubMed

135.

Zarranz JJ, Ferrer I, Lezcano E, Forcadas MI, Eizaguirre B, Atares B et al (2005) A novel mutation (K317M) in the MAPT gene causes FTDP and motor neuron disease. Neurology 64:1578–1585PubMed

136.

Zelaya MV, Pérez-Valderrama E, de Morentin XM, Tuñon T, Ferrer I, Luquin MR et al (2015) Olfactory bulb proteome dynamics during the progression of sporadic Alzheimer's disease: identification of common and distinct olfactory targets across Alzheimer-related co-pathologies. Oncotarget 6:39437–39456PubMedPubMedCentral

137.

Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S et al (2015) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34:11929–11947. (Erratum in: J Neurosci 35:846)

138.

Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O et al (2019) Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 10:1523PubMedPubMedCentral

Title: Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy
Authors: Isidro Ferrer
Pol Andrés-Benito
Maria Victoria Zelaya
Maria Elena Erro Aguirre
Margarita Carmona
Karina Ausín
Mercedes Lachén-Montes
Joaquín Fernández-Irigoyen
Enrique Santamaría
José Antonio del Rio
Publication date: 01-04-2020
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 4/2020
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-02122-9

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

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