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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-8976

AbdAlla, S; Lother, H; El Missiry, A; Langer, A; Sergeev, P; El Faramawy, Y; Quitterer, U (2009). Angiotensin II AT2 receptor oligomers mediate G-protein dysfunction in an animal model of Alzheimers disease. Journal of Biological Chemistry, 284(10):6554-6565.

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Abstract

Progressive neurodegeneration and decline of cognitive functions are major hallmarks of Alzheimer;s disease (AD). Neurodegeneration in AD correlates with dysfunction of diverse signal transduction mechanisms such as the G-protein-stimulated phosphoinositide hydrolysis mediated by Gaq/11. We report here that impaired Gaq/11-stimulated signaling in brain of AD patients and mice correlated with the appearance of cross-linked oligomeric angiotensin II AT2 receptors sequestering Gaq/11. Amyloid ss (Ass) was causal to AT2 oligomerization because cerebral microinjection of Ass triggered AT2 oligomerization in the hippocampus of mice in a dose-dependent manner. Ass 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 Gaq/11 dysfunction and enhanced neurodegeneration. Vice versa, stereotactic inhibition of AT2 oligomers by RNA interference prevented the impairment of Gaq/11, and delayed tau phosphorylation. Thus, Ass induces the formation of cross-linked AT2 oligomers that contribute to the dysfunction of Gaq/11 in an animal model of Alzheimer;s disease.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:6 March 2009
Deposited On:08 Jan 2009 09:54
Last Modified:27 Nov 2013 16:25
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
Additional Information:This research was originally published in AbdAlla, S; Lother, H; El Missiry, A; Langer, A; Sergeev, P; El Faramawy, Y; Quitterer, U (2009). Angiotensin II AT2 receptor oligomers mediate G-protein dysfunction in an animal model of Alzheimers disease. Journal of Biological Chemistry, 284(10):6554-6565. © the American Society for Biochemistry and Molecular Biology.
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1074/jbc.M807746200
PubMed ID:19074441

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