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 alpha-secretase precludes formation of neurotoxic Ab peptides and is expected to counteract the development of AD. An established approach for the up-regulation of alpha-secretase cleavage is the activation of G protein-coupled receptors (GPCRs). Therefore, our study aimed to analyze whether stimulation of angiotensin AT(1) or AT(2) receptors 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 AT(1) receptor increased several fold the a-secretase-mediated shedding of APP. This effect was completely abolished by treatment with the AT1 receptor-specific antagonist telmisartan. Using the BIM-46187 inhibitor, we demonstrate that the G alpha q protein-mediated pathway is involved in this stimulation process. Stimulation of AT1 receptors with the beta-arrestinbiased agonist SII was ineffective regarding alpha-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 G beta gamma 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/AT(1) receptor stimulation is effected by G protein activation with G beta gamma subunits playing important roles.
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