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.