Crosstalk between angiotensin and the nonamyloidogenic pathway of Alzheimer's amyloid precursor protein

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 AT1 or AT2 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 AT1 receptor increased several fold the α‐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 Gαq protein‐mediated pathway is involved in this stimulation process. Stimulation of AT1 receptors 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/AT1 receptor stimulation is effected by G protein activation with Gβγ subunits playing important roles. A link between Alzheimer´s disease and hypertension is well established. The angiotensin II type 1 (AT1) receptor is a key regulator of blood pressure and its signaling is conducted by G protein and β‐arrestin pathways. We report that AT1 receptor stimulation via angiotensin II induces the nonamyloidogenic processing of the amyloid precursor protein (APP) solely through the G protein‐dependent pathway and the α‐secretase ADAM10.