title: Pyroglutamate-modified amyloid-β protein demonstrates similar properties in an Alzheimer's disease familial mutant knock-in mouse and Alzheimer's disease brain.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular Biomarkers, Merck Research Laboratories, Merck & Co., West Point, Pa., USA.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Wu
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Miller
authors.forename: Brett
authors.initials: B
authors.lastname: Connolly
authors.forename: Jacob
authors.initials: J
authors.lastname: Marcus
authors.forename: John
authors.initials: J
authors.lastname: Renger
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Savage
mesh_terms: D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000906:Antibodies; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D055879:Gene Knock-In Techniques; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D053764:Presenilin-1; D011761:Pyrrolidonecarboxylic Acid