Pyroglutamate amyloid β(aβ) aggravates behavioral deficits in transgenic amyloid mouse model for Alzheimer disease

Abstract

Pyroglutamate-modified Aβ peptides at amino acid position three (Aβ pE3-42) are gaining considerable attention as potential key players in the pathogenesis of Alzheimer disease (AD). Aβ pE3-42 is abundant in AD brain and has a high aggregation propensity, stability and cellular toxicity. The aim of the present work wastostudythedirecteffectofelevated Aβ pE3-42 levelsonongoing ADpathology using transgenicmousemodels.Tothis end,wegenerated a novel mouse model (TBA42) that produces Aβ pE3-42. TBA42 mice showed age-dependent behavioral deficits and Aβ pE3-42 accumulation. The Aβ 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 Aβ peptides: Aβ 1-42, Aβ 1-40, Aβ pE3-40, Aβ pE3-42, Aβ 3-42, Aβ 4-42, and Aβ 5-42. 5XFAD and TBA42 mice were then crossed to generate transgenic FAD42 mice. At 6months of age, FAD42 mice showed an aggravated behavioral phenotype compared with single transgenic 5XFAD or TBA42 mice. ELISA and plaque load measurements revealed thatAβ pE3 levels were elevated in FAD42 mice. No change in Aβ x-42 or other Aβ isoforms was discovered by ELISA and mass spectrometry. These observations argue for a seeding effect of Aβ pE-42 in FAD42 mice. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.