Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

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}pharma.ethz.ch.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Inhibition of G-protein-coupled Receptor Kinase 2 (GRK2) Triggers the Growth-promoting Mitogen-activated Protein Kinase (MAPK) Pathway.
X. Fu, S. Koller, J. Abd Alla, and U. Quitterer (2013)
J. Biol. Chem. 288, 7738-7755
   Abstract »    Full Text »    PDF »
Neurotoxicity and Memory Deficits Induced by Soluble Low-Molecular-Weight Amyloid-{beta}1-42 Oligomers Are Revealed In Vivo by Using a Novel Animal Model.
J. Brouillette, R. Caillierez, N. Zommer, C. Alves-Pires, I. Benilova, D. Blum, B. De Strooper, and L. Buee (2012)
J. Neurosci. 32, 7852-7861
   Abstract »    Full Text »    PDF »
Binding of amyloid {beta} peptide to {beta}2 adrenergic receptor induces PKA-dependent AMPA receptor hyperactivity.
D. Wang, G. Govindaiah, R. Liu, V. De Arcangelis, C. L. Cox, and Y. K. Xiang (2010)
FASEB J 24, 3511-3521
   Abstract »    Full Text »    PDF »
Angiotensin-converting Enzyme Inhibition Down-regulates the Pro-atherogenic Chemokine Receptor 9 (CCR9)-Chemokine Ligand 25 (CCL25) Axis.
J. Abd Alla, A. Langer, S. S. Elzahwy, G. Arman-Kalcek, T. Streichert, and U. Quitterer (2010)
J. Biol. Chem. 285, 23496-23505
   Abstract »    Full Text »    PDF »
G Protein-Coupled Receptors, Cholinergic Dysfunction, and A{beta} Toxicity in Alzheimer's Disease.
A. Thathiah and B. De Strooper (2009)
Science Signaling 2, re8
   Abstract »    Full Text »    PDF »
Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders.
S. E. Iismaa, B. M. Mearns, L. Lorand, and R. M. Graham (2009)
Physiol Rev 89, 991-1023
   Abstract »    Full Text »    PDF »
Dominant Negative AT2 Receptor Oligomers Induce G-protein Arrest and Symptoms of Neurodegeneration.
S. AbdAlla, H. Lother, A. el Missiry, P. Sergeev, A. Langer, Y. el Faramawy, and U. Quitterer (2009)
J. Biol. Chem. 284, 6566-6574
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882