title: 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 was to study the direct effect of elevated Aβ(pE3-42) levels on ongoing AD pathology using transgenic mouse models. To this end, we generated 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 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 Aβ(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.
authors.affiliation: Division of Molecular Psychiatry, Georg August University Göttingen, University Medicine Göttingen, 37075 Göttingen, Germany.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Wittnam
authors.forename: Erik
authors.initials: E
authors.lastname: Portelius
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.forename: Mikael K
authors.initials: MK
authors.lastname: Gustavsson
authors.forename: Stephan
authors.initials: S
authors.lastname: Schilling
authors.forename: Birgit
authors.initials: B
authors.lastname: Koch
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.forename: Oliver
authors.initials: O
authors.lastname: Wirths
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D011761:Pyrrolidonecarboxylic Acid