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 Galphaq/11. We report here that impaired Galphaq/11-stimulated signaling in brains of AD patients and mice correlated with the appearance of cross-linked oligomeric angiotensin II AT2 receptors sequestering Galphaq/11. Amyloid beta (Abeta) was causal to AT2 oligomerization, because cerebral microinjection of Abeta triggered AT2 oligomerization in the hippocampus of mice in a dose-dependent manner. Abeta 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 Galphaq/11 dysfunction and enhanced neurodegeneration. Vice versa, stereotactic inhibition of AT2 oligomers by RNA interference prevented the impairment of Galphaq/11 and delayed Tau phosphorylation. Thus, Abeta induces the formation of cross-linked AT2 oligomers that contribute to the dysfunction of Galphaq/11 in an animal model of Alzheimer disease.
AbdAlla
Said
S
Heinrich-Pette-Institute, Martinistrasse 52, D-20251 Hamburg, Germany.
Lother
Heinz
H
el Missiry
Ahmed
A
Langer
Andreas
A
Sergeev
Pavel
P
el Faramawy
Yasser
Y
Quitterer
Ursula
U
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D016229:Amyloid beta-Peptides; D044139:Receptor, Angiotensin, Type 2; D043802:GTP-Binding Protein alpha Subunits, Gq-G11