Angiotensin II AT2 receptor oligomers mediate G-protein dysfunction in an animal model of Alzheimer disease

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 Gαq/11. We report here that impaired Gα q/11-stimulated signaling in brains of AD patients and mice correlated with the appearance of crosslinked oligomeric angiotensin II AT2 receptors sequestering Gα 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 Gαq/11 dysfunction and enhanced neurodegeneration. Vice versa, stereotactic inhibition of AT2 oligomers by RNA interference prevented the impairment of Gαq/11 and delayed Tau phosphorylation. Thus, Aβ induces the formation of cross-linked AT2 oligomers that contribute to the dysfunction of Gαq/11 in an animal model of Alzheimer disease. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.