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J. Biol. Chem. 284 (10): 6554-6565

© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

Angiotensin II AT2 Receptor Oligomers Mediate G-protein Dysfunction in an Animal Model of Alzheimer Disease*

Said AbdAlla{ddagger}, Heinz Lother{ddagger}, Ahmed el Missiry§, Andreas Langer, Pavel Sergeev, Yasser el Faramawy{ddagger}, , and Ursula Quitterer1

{ddagger}Heinrich-Pette-Institute, Martinistrasse 52, D-20251 Hamburg, Germany, the §Medical Research Center, Ain Shams University Hospital, Cairo, Egypt, and the Department of Molecular Pharmacology, Swiss Federal Institute of Technology and University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland

Abstract: Progressive neurodegeneration and decline of cognitive functions are major hallmarks of Alzheimer disease (AD). Neurodegeneration in AD correlates with dysfunction of diverse signal transduction mechanisms, such as the G-protein-stimulated phosphoinositide hydrolysis mediated by G{alpha}q/11. We report here that impaired G{alpha}q/11-stimulated signaling in brains of AD patients and mice correlated with the appearance of cross-linked oligomeric angiotensin II AT2 receptors sequestering G{alpha}q/11. Amyloid β (Aβ) was causal to AT2 oligomerization, because cerebral microinjection of Aβ triggered AT2 oligomerization in the hippocampus of mice in a dose-dependent manner. Aβ induced AT2 oligomerization by a two-step process of oxidative and transglutaminase-dependent cross-linking. The induction of AT2 oligomers in a transgenic mouse model with AD-like symptoms was associated with G{alpha}q/11 dysfunction and enhanced neurodegeneration. Vice versa, stereotactic inhibition of AT2 oligomers by RNA interference prevented the impairment of G{alpha}q/11 and delayed Tau phosphorylation. Thus, Aβ induces the formation of cross-linked AT2 oligomers that contribute to the dysfunction of G{alpha}q/11 in an animal model of Alzheimer disease.

Received for publication October 7, 2008. Revision received December 11, 2008.

* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom correspondence should be addressed: Y17M70, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Fax: 41-44-635-6881; E-mail: ursula.quitterer{at}

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