Pyroglutamate amyloid ß (Aß) aggravates behavioral deficits in transgenic amyloid mouse model for Alzheimer disease.

Pyroglutamate-modified Aß peptides at amino acid position three (Aß(pE3-42)) are gaining considerable attention as potential key players in the pathogenesis of Alzheimer disease (AD). Aß(pE3-42) is abundant in AD brain and has a high aggregation propensity, stability and cellular toxicity. The aim of the present work was to study the direct effect of elevated Aß(pE3-42) levels on ongoing AD pathology using transgenic mouse models. To this end, we generated a novel mouse model (TBA42) that produces Aß(pE3-42). TBA42 mice showed age-dependent behavioral deficits and Aß(pE3-42) accumulation. The Aß profile of an established AD mouse model, 5XFAD, was characterized using immunoprecipitation followed by mass spectrometry. Brains from 5XFAD mice demonstrated a heterogeneous mixture of full-length, N-terminal truncated, and modified Aß peptides: Aß(1-42), Aß(1-40), Aß(pE3-40), Aß(pE3-42), Aß(3-42), Aß(4-42), and Aß(5-42). 5XFAD and TBA42 mice were then crossed to generate transgenic FAD42 mice. At 6 months of age, FAD42 mice showed an aggravated behavioral phenotype compared with single transgenic 5XFAD or TBA42 mice. ELISA and plaque load measurements revealed that Aß(pE3) levels were elevated in FAD42 mice. No change in Aß(x)(-42) or other Aß isoforms was discovered by ELISA and mass spectrometry. These observations argue for a seeding effect of Aß(pE-42) in FAD42 mice.