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 Gαq/11-stimulated signaling in brains of AD patients and mice correlated with the appearance of cross-linked oligomeric angiotensin II AT2 receptors sequestering Gαq/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. 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 Gαq/11-stimulated signaling in brains of AD patients and mice correlated with the appearance of cross-linked oligomeric angiotensin II AT2 receptors sequestering Gαq/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. Alzheimer disease (AD) 2The abbreviations used are: AD, Alzheimer disease; Aβ, amyloid β; APPSw mice, transgenic mice expressing human APP695 with the double mutation (K670N/M671L) that was identified in a Swedish family with early onset Alzheimer disease; GTPγS, guanosine 5′-O-(thiotriphosphate); CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; HA, hemagglutinin; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling; HEK, human embryonic kidney; RNAi, RNA interference. is a protein aggregation disease that is characterized by profound neuropathological changes in the brain, including neurodegeneration, neurofibrillary tangles, and the accumulation of fibrillar β-amyloid (Aβ) 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 (1Price J.L. Morris J.C. Ann. Neurol. 1999; 45: 358-368Crossref PubMed Scopus (1387) Google Scholar), neurodegeneration and neuronal loss of AD patients are associated with the major AD symptoms of memory impairment and dementia (2Gomez-Isla T. Hollister R. West H. Mui S. Growdon J.H. Petersen R.C. Parisi J.E. Hyman B.T. Ann. Neurol. 1997; 41: 17-24Crossref PubMed Scopus (1139) Google Scholar, 3Price J.L. Ko A.I. Wade M.J. Tsou S.K. McKeel D.W. Morris J.C. Arch. Neurol. 2001; 58: 1395-1402Crossref PubMed Scopus (464) Google Scholar). Neurodegeneration in AD is accompanied by dysfunction of diverse signal transduction mechanisms, such as the G-protein-stimulated phosphoinositide hydrolysis mediated by Gαq/11 (4Ferrari-DiLeo G. Flynn D.D. Life Sci. 1993; 53: PL439-PL444Crossref PubMed Scopus (58) Google Scholar, 5Fowler C.J. Cowburn R.F. Garlind A. Winblad B. O'Neill C. Mol. Cell Biochem. 1995; 149: 287-292Crossref PubMed Scopus (33) Google Scholar, 6Greenwood A.F. Powers R.E. Jope R.S. Neuroscience. 1995; 69: 125-138Crossref PubMed Scopus (73) Google Scholar, 7Jope R.S. Song L. Li X. Powers R. Neurobiol. Aging. 1994; 15: 221-226Crossref PubMed Scopus (78) Google Scholar, 8Tsang S.W. Lai M.K. Kirvell S. Francis P.T. Esiri M.M. Hope T. Chen C.P. Wong P.T. Neurobiol. Aging. 2006; 27: 1216-1223Crossref PubMed Scopus (83) Google Scholar). Gαq/11-stimulated signal transduction pathways are important for neuronal communication, synaptic plasticity, and neuronal survival (9Miura M. Watanabe M. Offermanns S. Simon M.I. Kano M. J. Neurosci. 2002; 22: 8379-8390Crossref PubMed Google Scholar, 10Wettschureck N. van der Stelt M. Tsubokawa H. Krestel H. Moers A. Petrosino S. Schütz G. Di Marzo V. Offermanns S. Mol. Cell. Biol. 2006; 26: 5888-5894Crossref PubMed Scopus (65) Google Scholar). Therefore, it is likely that the Gαq/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 (8Tsang S.W. Lai M.K. Kirvell S. Francis P.T. Esiri M.M. Hope T. Chen C.P. Wong P.T. Neurobiol. Aging. 2006; 27: 1216-1223Crossref PubMed Scopus (83) Google Scholar). 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 Gαq/11: (i) protein levels of Gαq/11 are not changed (7Jope R.S. Song L. Li X. Powers R. Neurobiol. Aging. 1994; 15: 221-226Crossref PubMed Scopus (78) Google Scholar); (ii) downstream receptor/G-protein-independent phosphoinositide hydrolysis is intact (7Jope R.S. Song L. Li X. Powers R. Neurobiol. Aging. 1994; 15: 221-226Crossref PubMed Scopus (78) Google Scholar); and (iii) receptor-mediated activation of other G-proteins, such as the Gαi/o proteins, is not affected (5Fowler C.J. Cowburn R.F. Garlind A. Winblad B. O'Neill C. Mol. Cell Biochem. 1995; 149: 287-292Crossref PubMed Scopus (33) Google Scholar). In view of a putative role in the pathogenesis, we investigated the mechanism accounting for defective Gαq/11 activation in AD. Gαq/11 activation is under control of specific receptors. Although most receptors interacting with Gαq/11 stimulate guanine nucleotide exchange and thereby trigger Gαq/11-mediated signaling, the angiotensin II AT2 receptor is inhibitory and capable of disrupting receptor-stimulated Gαq/11 activation under specific conditions (11AbdAlla S. Lother H. Abdel-tawab A.M. Quitterer U. J. Biol. Chem. 2001; 276: 39721-39726Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar). Moreover, several studies link the AT2 receptor to diverse neuronal functions related to behavior (12Ichiki T. Labosky P.A. Shiota C. Okuyama S. Imagawa Y. Fogo A. Niimura F. Ichikawa I. Hogan B.L. Inagami T. Nature. 1995; 377: 748-750Crossref PubMed Scopus (802) Google Scholar), apoptosis (13Shenoy U.V. Richards E.M. Huang X.-C. Sumners C. Endocrinology. 1999; 140: 500-509Crossref PubMed Scopus (75) Google Scholar), and memory (14Vervoort V.S. Beachem M.A. Edwards P.S. Ladd S. Miller K.E. de Mollerat X. Clarkson K. DuPont B. Schwartz C.E. Stevenson R.E. Boyd E. Srivastava A.K. Science. 2002; 296: 2401-2403PubMed Google Scholar). Focusing on the inhibitory AT2 receptor as a potential candidate accounting for defective Gαq/11 activation in AD, we identified cross-linked oligomeric AT2 receptors that form by a two-step cross-linking process triggered by aggregated Aβ. Functional Assays-Basal and stimulated binding of [35S]GTPγS (specific activity 1250 Ci/mmol; final concentration 0.5 nm) to Gαq/11 was determined in the presence of 0.1 μm GDP in a volume of 200 μl in with of human and mouse as S. Lother H. A. Y. Quitterer U. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), by of Gαq/11. The the activation of because the with Gαq/11 as determined in The of hydrolysis was in with of of human as A.F. Powers R.E. Jope R.S. Neuroscience. 1995; 69: 125-138Crossref PubMed Scopus (73) Google Scholar). activity was determined by a S. Lother H. A. Y. Quitterer U. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). of Gαq/11 by of AT2 was by a that was S. Lother H. Quitterer U. Nature. PubMed Scopus Google Scholar). of and in of and APPSw mice determined and aggregated Aβ levels and determined in and the of the of and APPSw mice a for and used for and (11AbdAlla S. Lother H. Abdel-tawab A.M. Quitterer U. J. Biol. Chem. 2001; 276: 39721-39726Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar, S. Lother H. A. Y. Quitterer U. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, S. Lother H. Quitterer U. Nature. PubMed Scopus Google an of the human AT2 an of the human mouse AT2 an of the human an of mouse the of and used to and of the with the (11AbdAlla S. Lother H. Abdel-tawab A.M. Quitterer U. J. Biol. Chem. 2001; 276: 39721-39726Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar, S. Lother H. A. Y. Quitterer U. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, S. Lother H. Quitterer U. Nature. PubMed Scopus Google Scholar). in Aβ in the of Aβ was by with in the presence of by and in by and in by at by S. Lother H. Quitterer U. Nature. PubMed Scopus Google Scholar). of by in with and was by at for at The and by final concentration for at The was by by with of The was in and for at and for at protein by under conditions and with by to as S. Lother H. A. Y. Quitterer U. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). of the to human and mouse proteins, used for of and Gαq/11. characterized in studies (11AbdAlla S. Lother H. Abdel-tawab A.M. Quitterer U. J. Biol. Chem. 2001; 276: 39721-39726Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar, S. Lother H. A. Y. Quitterer U. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, S. Lother H. Quitterer U. Nature. PubMed Scopus Google Scholar, S. Lother H. A. Quitterer U. 2001; PubMed Scopus Google Scholar). was by of by by enhanced of AT2 receptors was determined with of in and by for at with of in a volume of μl in the presence of a of the to by by with was in a The binding was with AT2 receptors in with a at with of AD to and patients used as a control was patients and control and the was by the of mice used in this human APP695 with the double mutation that was identified in a Swedish family with early onset Alzheimer disease K. S. C. Y. S. F. G. Science. PubMed Scopus Google Scholar). mice as a control for for the of expressing under control of the RNA with RNA II of AT2 The of with the was with a by of the of the determined by transduction of by stereotactic in mice, used transduction with of APPSw mice with was as K.E. M. J. 2006; PubMed Scopus Google Scholar), at of to in was for at was with with in the and to to and the of determined by with and APPSw mice, not of not in the of APPSw transgenic mice and with 0.1 by in the in and by and studies with and at for by S. Lother H. A. Y. Quitterer U. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). of AT2 and receptor with of (11AbdAlla S. Lother H. Abdel-tawab A.M. Quitterer U. J. Biol. Chem. 2001; 276: 39721-39726Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar, S. Lother H. A. Y. Quitterer U. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). for Aβ with with of the Aβ Tau was with with to protein was used as a of neuronal and determined in with a with a was at of by of of the and of was with brains of APPSw mice into the of μl of a transduction of was by by (specific activity and of and receptors was with of and brains APPSw mice to for of AT2 and and by with and and with with a with a of and Aβ of in the hippocampus of APPSw transgenic mice was induced by stereotactic of μl of a under control of the into the of the hippocampus to as E. L. E. Neurosci. PubMed Scopus Google Scholar). mice on a stereotactic determined to the and the was with a with a and transduction a with a at a of The control of APPSw transgenic mice of a control of APPSw transgenic the mice brains and of mice and and Gαq/11 activity with the of AT2 a that a the of AT2 by RNA interference was into the of the hippocampus of APPSw mice as The control of a control of mice to the for the and as levels of in with with mice with a control the of Aβ on AT2 oligomerization in the of the in μl under into the of the hippocampus of mice as I. R. M.J. Nature. 2002; PubMed Scopus Google Scholar, J. Sci. U. S. A. PubMed Scopus Google Scholar). was used as the of AT2 receptors was by of the of APPSw transgenic mice into was in conditions and the other was to as S. A. Simon 1995; PubMed Scopus Google Scholar). The in a for of a for a for a on for the a in the for a for a mice with a in of with in the mice also a in levels of APPSw mice and 0.5 of APPSw of the of the brains and APPSw mice and for and as of used for used the to for memory J. Nature. PubMed Scopus Google Scholar). the the the of memory was determined in a for the was studies as 2002; PubMed Scopus Google Scholar). and by the on animal at the of and and in with of are as we the of Gαq/11-stimulated on of AD of AD patients with levels of amyloid β (Aβ) of Aβ to the G-protein signaling of AD patients characterized by impaired signaling, as by phosphoinositide hydrolysis under conditions with the receptor and the G-protein of by was not AD and not the phosphoinositide signal not with AD patients of defective Gαq/11-stimulated phosphoinositide signaling in AD (4Ferrari-DiLeo G. Flynn D.D. Life Sci. 1993; 53: PL439-PL444Crossref PubMed Scopus (58) Google Scholar, 5Fowler C.J. Cowburn R.F. Garlind A. Winblad B. O'Neill C. Mol. Cell Biochem. 1995; 149: 287-292Crossref PubMed Scopus (33) Google Scholar, 6Greenwood A.F. Powers R.E. Jope R.S. Neuroscience. 1995; 69: 125-138Crossref PubMed Scopus (73) Google Scholar, 7Jope R.S. Song L. Li X. Powers R. Neurobiol. Aging. 1994; 15: 221-226Crossref PubMed Scopus (78) Google Scholar, 8Tsang S.W. Lai M.K. Kirvell S. Francis P.T. Esiri M.M. Hope T. Chen C.P. Wong P.T. Neurobiol. Aging. 2006; 27: 1216-1223Crossref PubMed Scopus (83) Google Scholar). AT2 in AD that the neuronal angiotensin II AT2 receptor in the Gαq/11 signaling defect of AD because the AT2 receptor is of the inhibitory receptors capable of disrupting receptor-stimulated Gαq/11 activation under specific conditions (11AbdAlla S. Lother H. Abdel-tawab A.M. Quitterer U. J. Biol. Chem. 2001; 276: 39721-39726Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar). Moreover, several studies link the AT2 receptor to cerebral functions related to neuronal and memory (12Ichiki T. Labosky P.A. Shiota C. Okuyama S. Imagawa Y. Fogo A. Niimura F. Ichikawa I. Hogan B.L. Inagami T. Nature. 1995; 377: 748-750Crossref PubMed Scopus (802) Google Scholar, U.V. Richards E.M. Huang X.-C. Sumners C. Endocrinology. 1999; 140: 500-509Crossref PubMed Scopus (75) Google Scholar, V.S. Beachem M.A. Edwards P.S. Ladd S. Miller K.E. de Mollerat X. Clarkson K. DuPont B. Schwartz C.E. Stevenson R.E. Boyd E. Srivastava A.K. Science. 2002; 296: 2401-2403PubMed Google Scholar). the AT2 receptor protein in we (11AbdAlla S. Lother H. Abdel-tawab A.M. Quitterer U. J. Biol. Chem. 2001; 276: 39721-39726Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar). The with the AT2 receptor of of human embryonic AT2 was in the control AT2 receptors in as a of receptor levels protein In to the AT2 receptor of the AT2 protein on AD levels of a AT2 receptor of under conditions of In to the AT2 the AT2 receptor of and of an form of detected The AT2 receptor was on of control of the with the the specific a control and in agreement with (7Jope R.S. Song L. Li X. Powers R. Neurobiol. Aging. 1994; 15: 221-226Crossref PubMed Scopus (78) Google Scholar), protein levels of Gαq/11 the and not AT2 and Gαq/11 levels not a oligomeric AT2 receptor protein in AD patients that is in In to the AT2 the receptor on of AD patients as a detected in with Thus, AT2 receptors are in AD, the related receptor is not of Gαq/11 by AT2 in AD oligomeric AT2 receptor on of AD patients to Gαq/11 in the of as determined by AT2 receptors of control not with Gαq/11 The of oligomeric AT2 with Gαq/11 in AD was by Gαq/11 dysfunction as detected by Gαq/11 activation under conditions with that the AT2 of AD patients as a receptor that by S. F. M. J. J. PubMed Google Scholar). Aβ AT2 in the an of AT2 oligomers in the G-protein dysfunction of AD we investigated the of a causal AT2 oligomers and aggregated Aβ as a of AD. microinjection of Aβ to symptoms of cognitive impairment and neuronal I. R. M.J. Nature. 2002; PubMed Scopus Google Scholar, J. Sci. U. S. A. 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J.C. 1994; PubMed Scopus Google Scholar), Tau neuronal loss in the of APPSw mice with a of neuronal by in the of APPSw mice with mice accumulation of Tau was in the In agreement with a potential role of AT2 oligomers in AT2 receptor in that Thus, induced AT2 oligomerization and triggered a pathological of in APPSw mice that the AD of G-protein by AT2 and Gαq/11 in APPSw to AD patients AT2 oligomers of APPSw mice AT2 receptor and not with Gαq/11 and We the induction of AT2 oligomers to Gαq/11 Gαq/11 we the because impaired G-protein of correlates with disease severity in AD (8Tsang S.W. Lai M.K. Kirvell S. Francis P.T. Esiri M.M. Hope T. Chen C.P. Wong P.T. Neurobiol. Aging. 2006; 27: 1216-1223Crossref PubMed Scopus (83) Google Scholar). The stimulated the activation of Gαq/11 in the hippocampus of APPSw mice and and this signal was mediated by the receptor as by inhibition with the and The activation of Gαq/11 under conditions and was in APPSw mice with AT2 oligomers with APPSw mice Thus, APPSw mice with neurodegeneration AT2 oligomers and Gαq/11 the AT2 oligomers and impaired Gαq/11 we determined the of and of receptors in the and the of APPSw mice with neurodegeneration In the AT2 receptor was in of the hippocampus that also Tau of the of AT2 and investigated the of AT2 and of AT2 and receptors in of the hippocampus of APPSw mice that AT2 also for a of the with the the specific The levels of AT2 and receptors protein and not and not the of receptors and protein of and APPSw mice, not Thus, AT2 and receptors are in the of APPSw mice with impaired Gαq/11 of AT2 by RNA the of Gαq/11 and Tau AT2 receptors directly in the impairment of we the of AT2 in APPSw mice by RNA interference. of a into the the AT2 by a to a of AT2 as by the of was not affected and the of AT2 receptor oligomers was of the of Gαq/11 dysfunction was prevented to A. 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PubMed Scopus Google Scholar). for a causal role of AT2 receptor oligomers in the Gαq/11 dysfunction in Aβ and of AT2 in view of the of AT2 we determined the mechanism of AT2 two-step process to the formation of AT2 because cerebral microinjection of Aβ induced the of AT2 receptors in a dose-dependent mice of aggregated Aβ AT2 APPSw mice with levels of Aβ and cross-linked AT2 receptor and The cross-linking of AT2 receptors leading to was to as a of aggregated Aβ PubMed Scopus Google Scholar), because of Aβ by with an Aβ by with to levels of AT2 receptor and and and We that the oxidative AT2 receptors for cross-linking by a because are capable of cross-linking receptors S. Lother H. A. Y. Quitterer U. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), and activity is a of AD with neurodegeneration Miller Powers R.E. 1997; PubMed Scopus Google Scholar, A. G. C. G. Neurobiol. 2002; PubMed Scopus Google Scholar). In agreement with this the formation of AT2 oligomers was by the of in APPSw mice Aβ aggregation and in mice cerebral microinjection of of Aβ Vice versa, of in APPSw transgenic mice AT2 oligomers and by stereotactic of a into the of the hippocampus and was not by as a of neuronal also induced AT2 oligomers and Gαq/11 dysfunction Thus, for the formation of AT2 oligomers in in APPSw the are with a two-step process leading to AT2 oligomers in In a AT2 receptors are by In a the AT2 receptors are by in are related to the of AD by the induction of and activity with of Aβ. The identified and characterized AT2 receptor oligomers in brains of AD patients and AT2 receptor oligomers in by a two-step process of oxidative and transglutaminase-dependent cross-linking that is triggered by Aβ in a dose-dependent manner. oxidative cross-linking for the formation of AT2 receptor The of AT2 is to the of AD, because is to levels of as a of Aβ of Aβ and of APPSw transgenic mice the of AT2 AT2 oxidative cross-linking the for the cross-linking leading to AT2 on the cross-linking is also to aggregated Aβ and the of AD, because activity is in the brains of AD patients Miller Powers R.E. 1997; PubMed Scopus Google Scholar, A. G. C. G. Neurobiol. 2002; PubMed Scopus Google Scholar), and cerebral microinjection of Aβ of Aβ in APPSw transgenic mice was accompanied by the of AT2 oligomers to contribute to the Gαq/11 dysfunction in (i) impaired activation of Gαq/11 in of AD patients and of mice with AD-like correlated with the appearance of AT2 (ii) the formation of AT2 oligomers was to the of AD, because and for the formation of AT2 and (iii) stereotactic inhibition of cross-linked AT2 oligomers by RNA interference a AT2 receptor S. Lother H. A. A. Y. Quitterer U. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google prevented the of Gαq/11 sequestering Gαq/11 proteins, AT2 oligomers of AD patients and mice to as because AT2 oligomers induced the of a in S. Lother H. A. A. Y. Quitterer U. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Although the defect is a of AD in patients (4Ferrari-DiLeo G. Flynn D.D. Life Sci. 1993; 53: PL439-PL444Crossref PubMed Scopus (58) Google Scholar, 5Fowler C.J. Cowburn R.F. Garlind A. Winblad B. O'Neill C. Mol. Cell Biochem. 1995; 149: 287-292Crossref PubMed Scopus (33) Google Scholar, 6Greenwood A.F. Powers R.E. Jope R.S. Neuroscience. 1995; 69: 125-138Crossref PubMed Scopus (73) Google Scholar, 7Jope R.S. Song L. Li X. Powers R. Neurobiol. Aging. 1994; 15: 221-226Crossref PubMed Scopus (78) Google Scholar, 8Tsang S.W. Lai M.K. Kirvell S. Francis P.T. Esiri M.M. Hope T. Chen C.P. Wong P.T. Neurobiol. Aging. 2006; 27: 1216-1223Crossref PubMed Scopus (83) Google Scholar), role is barely understood. Gαq/11 dysfunction and the of AD leading to neurodegeneration and dementia is by the important role of Gαq/11 in neuronal survival and memory (9Miura M. Watanabe M. Offermanns S. Simon M.I. Kano M. J. Neurosci. 2002; 22: 8379-8390Crossref PubMed Google Scholar, 10Wettschureck N. van der Stelt M. Tsubokawa H. Krestel H. Moers A. Petrosino S. Schütz G. Di Marzo V. Offermanns S. Mol. Cell. Biol. 2006; 26: 5888-5894Crossref PubMed Scopus (65) Google Scholar, J. PubMed Scopus Google Scholar, A. N. Offermanns S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In of the of in mice are mediated by receptors J. PubMed Scopus Google Scholar). The receptor is a major of Gαq/11 dysfunction of AD and impaired Gαq/11 of receptors correlates with disease severity (8Tsang S.W. Lai M.K. Kirvell S. Francis P.T. Esiri M.M. Hope T. Chen C.P. Wong P.T. Neurobiol. Aging. 2006; 27: 1216-1223Crossref PubMed Scopus (83) Google Scholar). The a role of the Gαq/11 signaling defect in AD, because AT2 receptor oligomers to of the process the of AD. (i) of aggregated Aβ the formation of AT2 oligomers (ii) The induced AT2 oligomers G-protein and (iii) The impairment of signaling N. van der Stelt M. Tsubokawa H. Krestel H. Moers A. Petrosino S. Schütz G. Di Marzo V. Offermanns S. Mol. Cell. Biol. 2006; 26: 5888-5894Crossref PubMed Scopus (65) Google Scholar, A. N. Offermanns S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google the as by a Tau and Aβ aggregation of AT2 a role of AT2 receptor oligomers in neurodegeneration specific inhibition of AT2 oligomerization by an AT2 delayed the of symptoms in S. Lother H. A. A. Y. Quitterer U. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google AT2 oligomers a of neurodegeneration in AD.