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 he...

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Bibliographic Details
Published in:The Journal of biological chemistry 2009-03, Vol.284 (10), p.6554-6565
Main Authors: AbdAlla, Said, Lother, Heinz, el Missiry, Ahmed, Langer, Andreas, Sergeev, Pavel, el Faramawy, Yasser, Quitterer, Ursula
Format: Article
Language:English
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
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M807746200