Pyroglutamate-modified amyloid-β protein demonstrates similar properties in an Alzheimer's disease familial mutant knock-in mouse and Alzheimer's disease brain

Neurodegener Dis. 2014;14(2):53-66. doi: 10.1159/000353634. Epub 2013 Oct 23.


Background: N-terminally truncated, pyroglutamate-modified amyloid-β (Aβ) peptides are major constituents of amyloid deposits in Alzheimer's disease (AD).

Methods: Using a newly developed ELISA for Aβ modified at glutamate 3 with a pyroglutamate (pE3Aβ), brain pE3Aβ was characterized in human AD in an AD mouse model harboring double knock-in amyloid precursor protein (APP)-KM670/671NL and presenilin 1 (PS1)-P264L (APP/PS1-dKI) mutations, and in a second mouse model with transgenic overexpression of human APP695 with APP-KM670/671NL (Tg2576).

Results: pE3Aβ increased in the AD brain versus age-matched controls, with pE3Aβ/total Aβ at 45 and 10%, respectively. Compared to controls, the AD brain demonstrated 8.5-fold increased pE3Aβ compared to non-pE3Aβ species, which increased 2.7-fold. In the APP/PS1-dKI brain, pE3Aβ/total Aβ increased from 7% at 3 months to 16 and 19% at 15 and 19 months, respectively. In Tg2576, pE3Aβ/total Aβ was only 1.5% at 19 months, suggesting that APP/PS1-dKI, despite less total Aβ compared to Tg2576 at comparable ages, more closely mimics AD brain pathology.

Conclusion: This report supports a significant role for pE3Aβ in AD pathogenesis by confirming that pE3Aβ represents a large fraction of Aβ within the AD brain. Compared to the age-matched control brain, pE3Aβ increased to a greater extent compared to Aβ species without this N-terminal modification. Further, the APP/PS1-dKI model more closely resembles the AD brain in this regard, compared to the Tg2576 model.

MeSH terms

  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / immunology
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Antibodies
  • Brain / metabolism*
  • Disease Models, Animal*
  • Enzyme-Linked Immunosorbent Assay
  • Gene Knock-In Techniques
  • Humans
  • Mice
  • Mice, Transgenic
  • Presenilin-1 / genetics
  • Pyrrolidonecarboxylic Acid / chemistry


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Antibodies
  • Presenilin-1
  • Pyrrolidonecarboxylic Acid