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Acta Neuropathologica

, Volume 128, Issue 1, pp 67–79 | Cite as

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

  • Markus Mandler
  • Lauren Walker
  • Radmila Santic
  • Peter Hanson
  • Ajeet Rijal Upadhaya
  • Sean J. Colloby
  • Christopher M. Morris
  • Dietmar R. Thal
  • Alan J. Thomas
  • Achim Schneeberger
  • Johannes AttemsEmail author
Original Paper

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.

Keywords

Alzheimer’s disease Amyloid-β Hyperphosphorylated tau Pyroglutamylated amyloid-β 

Notes

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.

Supplementary material

401_2014_1296_MOESM1_ESM.pdf (23.8 mb)
Supplementary material 1 (PDF 24320 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Markus Mandler
    • 1
  • Lauren Walker
    • 2
  • Radmila Santic
    • 1
  • Peter Hanson
    • 4
  • Ajeet Rijal Upadhaya
    • 3
  • Sean J. Colloby
    • 2
  • Christopher M. Morris
    • 4
  • Dietmar R. Thal
    • 3
  • Alan J. Thomas
    • 2
  • Achim Schneeberger
    • 1
  • Johannes Attems
    • 2
    Email author
  1. 1.AFFiRiS AG, Vienna BiocenterViennaAustria
  2. 2.Institute for Ageing and HealthNewcastle University, Campus for Ageing and VitalityNewcastle upon TyneUK
  3. 3.Laboratory of Neuropathology, Center for Clinical Research, Institute of PathologyUniversity of UlmUlmGermany
  4. 4.Institute of NeuroscienceNewcastle UniversityNewcastle upon TyneUK

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