Editors' ChoiceNeuroscience

Oligomers of Dementia

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Science Signaling  10 Mar 2009:
Vol. 2, Issue 61, pp. ec88
DOI: 10.1126/scisignal.261ec88

Impaired signaling through receptors coupled to Gαq/11, such as the muscarinic acetylcholine receptor, is associated with dementia and Alzheimer’s disease (AD). In a pair of papers, AbdAlla et al. report that sequestration of Gαq/11 in β-amyloid (Aβ)–induced oligomers of angiotensin II receptors (AT2R) may contribute to the progression of AD. By comparing samples of prefrontal cortex from patients with AD and control patients, the author found decreased signaling (phosphoinositide hydrolysis) in response to either carbachol (muscarinic receptor agonist) or direct G protein activators, as well as decreased activation of Gαq/11. Western blots of the samples from AD patients also showed oligomeric AT2R associated with Gαq/11, whereas control brain samples had only monomeric AT2R that was not associated with Gαq/11. Cerebral injection of Aβ into mice produced a dose-dependent increase in oligomeric AT2R. The formation of oligomers was blocked by treatment with antioxidant, and Gαq/11-associated oligomers were induced by injection of transglutaminase, which suggests that oxidation followed by transglutamination underlies oligomer formation. By subjecting APPSw mice (a mouse model of AD) to stress, which accelerates disease progression, the authors showed that, compared with unstressed APPSw mice, the brains of the stressed mice had increased production of insoluble Aβ, oligomerization of AT2R associated with Gαq/11, and neurodegeneration, as well as impaired learning. Signaling in response to carbachol was also diminished in stressed APPSw mice. If AT2R was knocked down by hippocampal injection of RNAi, then insoluble Aβ formation and Tau phosphorylation were decreased and signaling through muscarinic receptors was retained in the stressed APPSw mice. In the second paper, AbdAlla et al. expressed AT2R and various mutants in human embryonic kidney (HEK) 293 cells to show that tyrosine residues in the cytoplasmic loop between transmembrane helices III and IV were necessary for the oxidative induction of dimers and that transglutamination to form oligomers required the C-terminal domain. Using the heterologous expression system, they also confirmed that AT2R oligomers sequestered Gαq/11 and inhibited muscarinic receptor signaling. Expression of a C-terminal truncated mutant AT2R prevented oligomerization of the receptor and restored muscarinic receptor responsiveness in the heterologous expression system. Viral delivery of this C-terminal truncation mutant into the hippocampus of stressed APPSw mice decreased AT2R oligomerization, decreased neurodegeneration, improved learning, and restored Gαq/11 activation, providing further support for AT2R oligomerization in progression of AD.

S. AbdAlla, H. Lother, A. el Missiry, A. Langer, P. Sergeev, Y. el Faramawy, U. Quitterer, Angiotensin II AT2 receptor oligomers mediate G-protein dysfunction in an animal model of Alzheimer disease. J. Biol. Chem. 284, 6554–6565 (2009). [Abstract] [Full Text]

S. AbdAlla, H. Lother, A. el Missiry, P. Sergeev, A. Langer, Y. el Faramawy, U. Quitterer, Dominant negative AT2 receptor oligomers induce G-protein arrest and symptoms of neurodegeneration. J. Biol. Chem. 284, 6566–6574 (2009). [Abstract] [Full Text]

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