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.
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.
|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
|Date:||06 March 2009|
|Deposited On:||08 Jan 2009 10:54|
|Last Modified:||23 Nov 2012 13:28|
|Publisher:||American Society for Biochemistry and Molecular Biology|
|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.|
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