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 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 crosslinked oligomeric angiotensin II AT(2) receptors sequestering G alpha(q/11). Amyloid beta (A beta) was causal to AT(2) oligomerization, because cerebral microinjection of A beta triggered AT(2) oligomerization in the hippocampus of mice in a dose- dependent manner. A beta induced AT(2) oligomerization by a two-step process of oxidative and transglutaminase-dependent cross-linking. The induction of AT(2) 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 AT(2) oligomers by RNA interference prevented the impairment of G alpha(q/11) and delayed Tau phosphorylation. Thus, A beta induces the formation of cross-linked AT(2) oligomers that contribute to the dysfunction of G alpha(q/11) in an animal model of Alzheimer disease.