title: Crosstalk between angiotensin and the nonamyloidogenic pathway of Alzheimer's amyloid precursor protein.
abstract: The association between hypertension and an increased risk for Alzheimer's disease (AD) and dementia is well established. Many data suggest that modulation of the renin-angiotensin system may be meaningful for the prevention and therapy of neurodegenerative disorders, in particular AD. Proteolytic cleavage of the amyloid precursor protein (APP) by α-secretase precludes formation of neurotoxic Aβ peptides and is expected to counteract the development of AD. An established approach for the up-regulation of α-secretase cleavage is the activation of G protein-coupled receptors (GPCRs). Therefore, our study aimed to analyze whether stimulation of angiotensin AT1or AT2receptors stably expressed in HEK cells influence the nonamyloidogenic pathway of APP processing. Treatment of both receptors with angiotensin II clearly showed that only activation of the AT1receptor increased several fold the α-secretase-mediated shedding of APP. This effect was completely abolished by treatment with the AT1receptor-specific antagonist telmisartan. Using the BIM-46187 inhibitor, we demonstrate that the Gαq protein-mediated pathway is involved in this stimulation process. Stimulation of AT1receptors with the β-arrestin-biased agonist SII was ineffective regarding α-secretase-mediated APP shedding. This result discloses that only the G protein-dependent pathway is involved in the Ang II-induced APP shedding. Blocking of Gβγ subunits by the inhibitor gallein completely prevented constitutive and Ang II-induced APP shedding. Our findings provide evidence that induction of APP shedding via Ang II/AT1receptor stimulation is effected by G protein activation with Gβγ subunits playing important roles.
authors.affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Kanarek
authors.affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry, University of Bonn, Germany.
authors.forename: Jim
authors.initials: J
authors.lastname: Küppers
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry, University of Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
authors.affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Postina
authors.affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Kojro
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000686:Amyloidosis / Q000235:genetics / Q000473:pathology; D000809:Angiotensins / Q000235:genetics / Q000378:metabolism*; D003510:Cyclohexanes / Q000008:administration & dosage; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D059748:Proteolysis / Q000187:drug effects; D011719:Pyrazines / Q000008:administration & dosage; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000378:metabolism; D000071557:beta-Arrestins / Q000819:agonists / Q000378:metabolism
chemical_list: C533004:7-(2-amino-1-oxo-3-thio-propyl)-8-cyclohexylmethyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-(1,2a)-pyrazine dimer, hydrochloride; D016564:Amyloid beta-Protein Precursor; D000809:Angiotensins; D003510:Cyclohexanes; D044385:GTP-Binding Protein alpha Subunits; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D011719:Pyrazines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000071557:beta-Arrestins; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; alpha-secretase ADAM10; angiotensin receptor; renin-angiotensin system