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

Acta Neuropathol. 2014 Jul;128(1):67-79. doi: 10.1007/s00401-014-1296-9. Epub 2014 May 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism*
  • Blotting, Western
  • Cell Membrane / metabolism
  • Entorhinal Cortex / metabolism*
  • Entorhinal Cortex / pathology
  • Female
  • Frontal Lobe / metabolism*
  • Frontal Lobe / pathology
  • Humans
  • Image Processing, Computer-Assisted
  • Male
  • Neuropsychological Tests
  • Peptide Fragments / metabolism*
  • Phosphorylation
  • Photomicrography
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • Severity of Illness Index
  • tau Proteins / metabolism*


  • Amyloid beta-Peptides
  • MAPT protein, human
  • Peptide Fragments
  • amyloid beta-protein (3-42), pyroglutamyl(3)-
  • tau Proteins