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Pyroglutamylated amyloid-β is associated with hyperphosphorylated tau and severity of Alzheimer’s disease

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Abstract

Pyroglutamylated amyloid-β (pE(3)-Aβ) has been suggested to play a major role in Alzheimer’s disease (AD) pathogenesis as amyloid-β (Aβ) oligomers containing pE(3)-Aβ might initiate tau-dependent cytotoxicity. We aimed to further elucidate the associations among pE(3)-Aβ, full-length Aβ and hyperphosphorylated tau (HP-τ) in human brain tissue. We examined 41 post mortem brains of both AD (n = 18) and controls. Sections from frontal and entorhinal cortices were stained with pE(3)-Aβ, HP-τ and full-length Aβ antibodies. The respective loads were assessed using image analysis and western blot analysis was performed in a subset of cases. All loads were significantly higher in AD, but when using Aβ loads as independent variables only frontal pE(3)-Aβ load predicted AD. In frontal and entorhinal cortices pE(3)-Aβ load independently predicted HP-τ load while non-pE(3)-Aβ failed to do so. All loads correlated with the severity of AD neuropathology. However, partial correlation analysis revealed respective correlations in the frontal cortex only for pE(3)-Aβ load only while in the entorhinal cortex respective correlations were seen for both HP-τ and non-pE(3)-Aβ loads. Mini Mental State Examination scores were independently predicted by entorhinal HP-τ load and by frontal pE(3)-Aβ load. Here, we report an association between pE(3)-Aβ and HP-τ in human brain tissue and an influence of frontal pE(3)-Aβ on both the severity of AD neuropathology and clinical dementia. Our findings further support the notion that pE(3)-Aβ may represent an important link between Aβ and HP-τ, and investigations into its role as diagnostic and therapeutic target in AD are warranted.

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References

  1. Acero G, Manoutcharian K, Vasilevko V, Munguia ME, Govezensky T, Coronas G, Luz-Madrigal A, Cribbs DH, Gevorkian G (2009) Immunodominant epitope and properties of pyroglutamate-modified Abeta-specific antibodies produced in rabbits. J Neuroimmunol 213:39–46

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Alexandru A, Jagla W, Graubner S, Becker A, Bauscher C, Kohlmann S, Sedlmeier R, Raber KA, Cynis H, Ronicke R, Reymann KG, Petrasch-Parwez E, Hartlage-Rubsamen M, Waniek A, Rossner S, Schilling S, Osmand AP, Demuth HU, von Horsten S (2011) Selective hippocampal neurodegeneration in transgenic mice expressing small amounts of truncated Abeta is induced by pyroglutamate-Abeta formation. J Neurosci 31:12790–12801

    Article  CAS  PubMed  Google Scholar 

  3. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 82:239–259

    Article  CAS  Google Scholar 

  4. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol (Berl) 112:389–404

    Article  Google Scholar 

  5. Cynis H, Scheel E, Saido TC, Schilling S, Demuth HU (2008) Amyloidogenic processing of amyloid precursor protein: evidence of a pivotal role of glutaminyl cyclase in generation of pyroglutamate-modified amyloid-β. Biochemistry 47:7405–7413

    Article  CAS  PubMed  Google Scholar 

  6. D’Arrigo C, Tabaton M, Perico A (2009) N-terminal truncated pyroglutamyl beta amyloid peptide Abetapy3–42 shows a faster aggregation kinetics than the full-length Abeta1–42. Biopolymers 91:861–873

    Article  PubMed  Google Scholar 

  7. Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118:5–36

    Article  CAS  PubMed  Google Scholar 

  8. Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198

    Article  CAS  PubMed  Google Scholar 

  9. Frost JL, Le KX, Cynis H, Ekpo E, Kleinschmidt M, Palmour RM, Ervin FR, Snigdha S, Cotman CW, Saido TC, Vassar RJ, St George-Hyslop P, Ikezu T, Schilling S, Demuth HU, Lemere CA (2013) Pyroglutamate-3 amyloid-β deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models. Am J Pathol 183:369–381

    Article  CAS  PubMed  Google Scholar 

  10. Gunn AP, Masters CL, Cherny RA (2010) Pyroglutamate-Abeta: role in the natural history of Alzheimer’s disease. Int J Biochem Cell Biol 42:1915–1918

    Article  CAS  PubMed  Google Scholar 

  11. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    Article  CAS  PubMed  Google Scholar 

  12. Harigaya Y, Saido TC, Eckman CB, Prada CM, Shoji M, Younkin SG (2000) Amyloid beta protein starting pyroglutamate at position 3 is a major component of the amyloid deposits in the Alzheimer’s disease brain. Biochem Biophys Res Commun 276:422–427

    Article  CAS  PubMed  Google Scholar 

  13. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL (1982) A new clinical scale for the staging of dementia. Br J Psychiatry 140:566–572

    Article  CAS  PubMed  Google Scholar 

  14. Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ (2011) Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci USA 108:5819–5824

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Mandler M, Rockenstein E, Ubhi K, Hansen L, Adame A, Michael S, Galasko D, Santic R, Mattner F, Masliah E (2012) Detection of peri-synaptic amyloid-β pyroglutamate aggregates in early stages of Alzheimer’s disease and in AbetaPP transgenic mice using a novel monoclonal antibody. J Alzheimers Dis 28:783–794

    CAS  PubMed  Google Scholar 

  16. Mc Donald JM, Savva GM, Brayne C, Welzel AT, Forster G, Shankar GM, Selkoe DJ, Ince PG, Walsh DM (2010) The presence of sodium dodecyl sulphate-stable Abeta dimers is strongly associated with Alzheimer-type dementia. Brain 133:1328–1341

    Article  PubMed Central  PubMed  Google Scholar 

  17. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944

    Article  CAS  PubMed  Google Scholar 

  18. Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Trojanowski JQ, Vinters HV, Hyman BT (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 123:1–11

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Morawski M, Schilling S, Kreuzberger M, Waniek A, Jager C, Koch B, Cynis H, Kehlen A, Arendt T, Hartlage-Rubsamen M, Demuth HU, Rossner S (2014) Glutaminyl cyclase in human cortex: correlation with (pGlu)-amyloid-β load and cognitive decline in Alzheimer’s disease. J Alzheimers Dis 39:385–400

  20. Nussbaum JM, Schilling S, Cynis H, Silva A, Swanson E, Wangsanut T, Tayler K, Wiltgen B, Hatami A, Ronicke R, Reymann K, Hutter-Paier B, Alexandru A, Jagla W, Graubner S, Glabe CG, Demuth HU, Bloom GS (2012) Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β. Nature 485:651–655

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Piccini A, Russo C, Gliozzi A, Relini A, Vitali A, Borghi R, Giliberto L, Armirotti A, D’Arrigo C, Bachi A, Cattaneo A, Canale C, Torrassa S, Saido TC, Markesbery W, Gambetti P, Tabaton M (2005) β-amyloid is different in normal aging and in Alzheimer disease. J Biol Chem 280:34186–34192

    Article  CAS  PubMed  Google Scholar 

  22. Rijal Upadhaya A, Capetillo-Zarate E, Kosterin I, Abramowski D, Kumar S, Yamaguchi H, Walter J, Fandrich M, Staufenbiel M, Thal DR (2012) Dispersible amyloid β-protein oligomers, protofibrils, and fibrils represent diffusible but not soluble aggregates: their role in neurodegeneration in amyloid precursor protein (APP) transgenic mice. Neurobiol Aging 33:2641–2660

    Article  CAS  PubMed  Google Scholar 

  23. Rijal Upadhaya A, Kosterin I, Kumar S, von Arnim CA, Yamaguchi H, Fandrich M, Walter J, Thal DR (2014) Biochemical stages of amyloid-β peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer’s disease. Brain 137:887–903

    Article  PubMed  Google Scholar 

  24. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L (2007) Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer’s disease mouse model. Science 316:750–754

    Article  CAS  PubMed  Google Scholar 

  25. Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, Wu T, Hamto P, Devidze N, Yu GQ, Palop JJ, Noebels JL, Mucke L (2011) Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer’s disease. J Neurosci 31:700–711

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Russo C, Violani E, Salis S, Venezia V, Dolcini V, Damonte G, Benatti U, D’Arrigo C, Patrone E, Carlo P, Schettini G (2002) Pyroglutamate-modified amyloid beta-peptides-AbetaN3(pE)-strongly affect cultured neuron and astrocyte survival. J Neurochem 82:1480–1489

    Article  CAS  PubMed  Google Scholar 

  27. Saido TC, Iwatsubo T, Mann DM, Shimada H, Ihara Y, Kawashima S (1995) Dominant and differential deposition of distinct β-amyloid peptide species, A beta N3(pE), in senile plaques. Neuron 14:457–466

    Article  CAS  PubMed  Google Scholar 

  28. Saido TC (1998) Alzheimer’s disease as proteolytic disorders: anabolism and catabolism of β-amyloid. Neurobiol Aging 19:S69–S75

    Article  CAS  PubMed  Google Scholar 

  29. Schilling S, Hoffmann T, Manhart S, Hoffmann M, Demuth HU (2004) Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions. FEBS Lett 563:191–196

    Article  CAS  PubMed  Google Scholar 

  30. Schilling S, Lauber T, Schaupp M, Manhart S, Scheel E, Bohm G, Demuth HU (2006) On the seeding and oligomerization of pGlu-amyloid peptides (in vitro). Biochemistry 45:12393–12399

    Article  CAS  PubMed  Google Scholar 

  31. Schilling S, Zeitschel U, Hoffmann T, Heiser U, Francke M, Kehlen A, Holzer M, Hutter-Paier B, Prokesch M, Windisch M, Jagla W, Schlenzig D, Lindner C, Rudolph T, Reuter G, Cynis H, Montag D, Demuth HU, Rossner S (2008) Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer’s disease-like pathology. Nat Med 14:1106–1111

    Article  CAS  PubMed  Google Scholar 

  32. Schlenzig D, Manhart S, Cinar Y, Kleinschmidt M, Hause G, Willbold D, Funke SA, Schilling S, Demuth HU (2009) Pyroglutamate formation influences solubility and amyloidogenicity of amyloid peptides. Biochemistry 48:7072–7078

    Article  CAS  PubMed  Google Scholar 

  33. Selkoe DJ (1989) Amyloid beta protein precursor and the pathogenesis of Alzheimer’s disease. Cell 58:611–612

    Article  CAS  PubMed  Google Scholar 

  34. Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A β-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800

    Article  PubMed  Google Scholar 

  35. Vossel KA, Zhang K, Brodbeck J, Daub AC, Sharma P, Finkbeiner S, Cui B, Mucke L (2010) Tau reduction prevents Abeta-induced defects in axonal transport. Science 330:198

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Watt AD, Perez KA, Rembach A, Sherrat NA, Hung LW, Johanssen T, McLean CA, Kok WM, Hutton CA, Fodero-Tavoletti M, Masters CL, Villemagne VL, Barnham KJ (2013) Oligomers, fact or artefact? SDS-PAGE induces dimerization of β-amyloid in human brain samples. Acta Neuropathol 125:549–564

    Article  CAS  PubMed  Google Scholar 

  37. Wirths O, Breyhan H, Cynis H, Schilling S, Demuth HU, Bayer TA (2009) Intraneuronal pyroglutamate-Abeta 3–42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model. Acta Neuropathol 118:487–496

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

We are very grateful to the individuals who kindly donated their brains to the Newcastle Brain Tissue Resource and to the brain collection of the University of Ulm. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre for Ageing and Age-related disease and the Biomedical Research Unit for Lewy body dementia based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University (R:CH/ML/0712). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Part of this study was supported by the Dunhill Medical Trust (R173/1110) and the Alzheimer Forschung Initiative (DRT: Project Numbers: #10810, #13803). Tissue for this study was provided by the Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK Medical Research Council (G0400074) and by Brains for Dementia research, a joint venture between Alzheimer’s Society and Alzheimer’s Research UK. We are grateful to Dr Craig Parker for his valuable help with biochemistry.

Conflict of interest

MM, RS and AS are employees of AFFiRiS AG, which provided the 84D antibody; otherwise, the authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. AFFiRiS AG, Vienna Biocenter, Karl-Farkas-Gasse 22, Vienna, Austria

    Markus Mandler, Radmila Santic & Achim Schneeberger

  2. Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, UK

    Lauren Walker, Sean J. Colloby, Alan J. Thomas & Johannes Attems

  3. Laboratory of Neuropathology, Center for Clinical Research, Institute of Pathology, University of Ulm, Ulm, Germany

    Ajeet Rijal Upadhaya & Dietmar R. Thal

  4. Institute of Neuroscience, Newcastle University, Claremont Place, Newcastle upon Tyne, NE2 4AA, UK

    Peter Hanson & Christopher M. Morris

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  1. Markus Mandler
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Correspondence to Johannes Attems.

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M. Mandler and L. Walker have contributed equally to this work.

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Mandler, M., Walker, L., Santic, R. et al. Pyroglutamylated amyloid-β is associated with hyperphosphorylated tau and severity of Alzheimer’s disease. Acta Neuropathol 128, 67–79 (2014). https://doi.org/10.1007/s00401-014-1296-9

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  • DOI: https://doi.org/10.1007/s00401-014-1296-9

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