Angiotensin II AT2 Receptor Oligomers Mediate G-protein Dysfunction in an Animal Model of Alzheimer Disease

• Published in: The Journal of biological chemistry Vol. 284; no. 10; pp. 6554 - 6565
• Main Authors: AbdAlla, Said, Lother, Heinz, el Missiry, Ahmed, Langer, Andreas, Sergeev, Pavel, el Faramawy, Yasser, Quitterer, Ursula
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06-03-2009; American Society for Biochemistry and Molecular Biology
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Animals; Disease Models, Animal; Female; GTP-Binding Protein alpha Subunits, Gq-G11 - genetics; GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism; Hippocampus - metabolism; Humans; Male; Mice; Mice, Transgenic; Middle Aged; Receptor, Angiotensin, Type 2 - genetics; Receptor, Angiotensin, Type 2 - metabolism; Signal Transduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M807746200

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.