Pyroglutamate Amyloid beta (A beta) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease
2012 | journal article. A publication with affiliation to the University of Göttingen.
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Pyroglutamate Amyloid beta (A beta) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease
Wittnam, J. L.; Portelius, E.; Zetterberg, H.; Gustavsson, M. K.; Schilling, S.; Koch, B. & Demuth, H.-U. et al. (2012)
Journal of Biological Chemistry, 287(11) pp. 8154-8162. DOI: https://doi.org/10.1074/jbc.M111.308601
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- Authors
- Wittnam, Jessica L.; Portelius, Erik; Zetterberg, Henrik; Gustavsson, Mikael K.; Schilling, Stephan; Koch, Birgit; Demuth, Hans-Ulrich; Blennow, Kaj; Wirths, Oliver; Bayer, Thomas A.
- Abstract
- Pyroglutamate-modified A beta peptides at amino acid position three (A beta(pE3-42)) are gaining considerable attention as potential key players in the pathogenesis of Alzheimer disease (AD). A beta(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 A beta(pE3-42) levels on ongoing AD pathology using transgenic mouse models. To this end, we generated a novel mouse model (TBA42) that produces A beta(pE3-42). TBA42 mice showed age-dependent behavioral deficits and A beta(pE3-42) accumulation. The A beta 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 A beta peptides: A beta(1-42), A beta(1-40), A beta(pE3-40), A beta(pE3-42), A beta(3-42), A beta(4-42), and A beta(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 A beta(pE3) levels were elevated in FAD42 mice. No change in A beta(x-42) or other A beta isoforms was discovered by ELISA and mass spectrometry. These observations argue for a seeding effect of A beta(pE-42) in FAD42 mice.
- Issue Date
- 2012
- Status
- published
- Publisher
- Amer Soc Biochemistry Molecular Biology Inc
- Journal
- Journal of Biological Chemistry
- ISSN
- 0021-9258