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␣ q/11 . We report here that impaired G␣ 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␣ q/11 . Amyloid ␤ (A␤) was causal to AT 2 oligomerization, because cerebral microinjection of A␤ triggered AT 2 oligomerization in the hippocampus of mice in a dose-dependent manner. A␤ 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␣ q/11 dysfunction and enhanced neurodegeneration. Vice versa, stereotactic inhibition of AT 2 oligomers by RNA interference prevented the impairment of G␣ q/11 and delayed Tau phosphorylation. Thus, A␤ induces the formation of cross-linked AT 2 oligomers that contribute to the dysfunction of G␣ q/11 in an animal model of Alzheimer disease. Alzheimer disease (AD)2 is a protein aggregation disease that is characterized by profound neuropathological changes in the brain, including neurodegeneration, neurofibrillary tangles, and the accumulation of fibrillar ␤-amyloid (A␤) in extracellular senile plaques. Although some neuropathological features of AD, such as tangles and plaques, are also detected in brains of elderly people without major symptoms of dementia (1), neurodegeneration and neuronal loss of AD patients are associated with the major AD symptoms of memory impairment and dementia (2, 3). Neurodegeneration in AD is accompanied by dysfunction of diverse signal transduction mechanisms, such as the G-protein-stimulated phosphoinositide hydrolysis mediated by G␣ q/11 (4 -8). G␣ q/11 -stimulated signal transduction pathways are important for neuronal communication, synaptic plasticity, and neuronal survival (9, 10). Therefore, it is likely that the G␣ q/11 signaling defect of AD patients plays a role in the disease process leading to neurodegeneration and dementia. In agreement with this notion, G-protein dysfunction is directly associated with disease severity of AD patients (8).Further insight into the pathological role of the G-protein dysfunction of AD patients is lacking, because the underlying mechanism is barely understood. Several observations point to a specific defect at the level of G␣ q/11 : (i) protein levels of G␣ q/11 are not changed (7); (ii) downstream receptor/G-protein-independent phosphoinositide hydrolysis is intact (7); and (iii) receptor-mediated activation of other G-proteins, such as the G␣ i/o proteins, is not affected (5). In view of a putative role in the pathogenesis, we investigated the mechanism accounting for defective G␣ q/11 activation in AD.G␣ q/11 activation is under control of specific receptors. Although mo...

Neurodegeneration in Alzheimer's disease (AD) correlates with dysfunction of signaling mediated by G␣ q/11 . Nondissociable angiotensin II AT 2 receptor oligomers are linked to the impaired G␣ q/11 -stimulated signaling of AD patients and transgenic mice with AD-like symptoms. To further analyze the role of AT 2 receptor oligomers, we induced the formation of AT 2 oligomers in an in vitro cell system. Similarly as in vivo, sequential oxidative and transglutaminase-dependent cross-linking steps triggered the formation of AT 2 oligomers in vitro. Elevated reactive oxygen species mediated oxidative cross-linking of AT 2 monomers to dimers involving tyrosine residues located at putative interreceptor contact sites of the cytoplasmic loop connecting transmembrane helices III/IV. Cross-linked AT 2 dimers were subsequently a substrate of activated transglutaminase-2, which targeted the carboxyl terminus of AT 2 dimers, as assessed by truncated and chimeric AT 2 receptors, respectively. AT 2 oligomers acted as dominant negative receptors in vitro by mediating G␣ q/11 protein sequestration and G␣ q/11 protein arrest. The formation of AT 2 oligomers and G-protein dysfunction could be suppressed in vitro and in vivo by an AT 2 receptor mutant. Inhibition of AT 2 oligomerization upon stereotactic expression of the AT 2 receptor mutant revealed that G␣ q/11 -sequestering AT 2 oligomers enhanced the development of neurodegenerative symptoms in the hippocampus of transgenic mice with AD-like pathology. Thus, AT 2 oligomers inducing G␣ q/11 arrest are causally involved in inducing symptoms of neurodegeneration.Dysfunction of G␣ q/11 is a characteristic feature of AD 2 patients and transgenic mice with AD-like symptoms (see the accompanying article (26) and Refs. 1-5). The G␣ q/11 -protein defect is a well established hallmark of clinical AD (5). However, the pathophysiological role of the G-protein defect is barely understood. A direct relationship between G␣ q/11 dysfunction and the pathogenesis of AD leading to neurodegeneration and dementia is suggested by the important role of G␣ q/11 proteins in neuronal survival and memory (6, 7). In addition, many of the cognition-enhancing effects of acetylcholine are mediated by the G␣ q/11 -coupled muscarinic receptors (8). The M 1 receptor is a major target of G␣ q/11 dysfunction of AD patients and mice, and impaired G␣ q/11 -coupling of M 1 receptors correlates with disease severity (5).To better understand the pathophysiological function of the G-protein defect in AD, we analyzed the mechanism accounting for the G-protein defect in AD. In the first article (26), we identified cross-linked AT 2 receptor oligomers in the brains of AD patients and transgenic mice with AD-like symptoms. Coenrichment studies showed that AT 2 receptor oligomers resembled dominant negative receptors by sequestering G␣ q/11 in the absence of agonist. The cross-linked AT 2 receptors were directly linked to the progression of AD, because (aggregated) amyloid ␤ (A␤) triggered AT 2 oligomerization in vivo in a...