Pyroglutamate-Modified Amyloid-β Protein Demonstrates Similar Properties in an Alzheimer's Disease Familial Mutant Knock-In Mouse and Alzheimer's Disease Brain

Background: N-terminally truncated, pyroglutamate-modified amyloid-beta (A beta) peptides are major constituents of amyloid deposits in Alzheimer's disease (AD). Methods: Using a newly developed ELISA for A beta modified at glutamate 3 with a pyroglutamate (pE3A beta), brain pE3A beta 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: pE3A beta increased in the AD brain versus age-matched controls, with pE3A beta/total A beta at 45 and 10%, respectively. Compared to controls, the AD brain demonstrated 8.5-fold increased pE3A beta compared to non-pE3A beta species, which increased 2.7-fold. In the APP/PS1-dKI brain, pE3A beta/total A beta increased from 7% at 3 months to 16 and 19% at 15 and 19 months, respectively. In Tg2576, pE3A beta/total A beta was only 1.5% at 19 months, suggesting that APP/PS1-dKI, despite less total A beta compared to Tg2576 at comparable ages, more closely mimics AD brain pathology. Conclusion: This report supports a significant role for pE3A beta in AD pathogenesis by confirming that pE3A beta represents a large fraction of A beta within the AD brain. Compared to the age-matched control brain, pE3A beta increased to a greater extent compared to A beta 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. (C) 2013 S. Karger AG, Basel