Crosstalk between angiotensin and the nonamyloidogenic pathway of Alzheimer's amyloid precursor protein
Crosstalk between angiotensin and the nonamyloidogenic pathway of Alzheimer's amyloid precursor protein
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DOI：
10.1111/febs.14015
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发表时间：
2017-03-01
期刊：
影响因子：
5.4
通讯作者：
Kojro, Elzbieta
中科院分区：
文献类型：
--
作者：
Kanarek, Anna Maria;Wagner, Annika;Kojro, Elzbieta
高血压与阿尔茨海默病（AD）和痴呆症风险增加之间的关联已得到充分证实。许多数据表明，调节肾素-血管紧张素系统可能对预防和治疗神经退行性疾病，特别是AD有意义。α-分泌酶对淀粉样前体蛋白（APP）的蛋白水解裂解排除了神经毒性Ab肽的形成，并有望抵消AD的发展。α-分泌酶裂解的上调的一种既定方法是G蛋白偶联受体（GPCR）的活化。因此，我们的研究旨在分析刺激HEK细胞中稳定表达的血管紧张素AT（1）或AT（2）受体是否会影响APP加工的非淀粉样蛋白生成途径。用血管紧张素II治疗两种受体清楚地表明，只有AT（1）受体的激活增加了几倍的α-分泌酶介导的APP脱落。这种作用被完全消除与AT 1受体特异性拮抗剂替米沙坦治疗。使用BIM-46187抑制剂，我们证明了G α q蛋白介导的途径参与了这一刺激过程。用β-arrestinbiased激动剂SII刺激AT 1受体对α-分泌酶介导的APP脱落无效。这一结果揭示了只有G蛋白依赖性途径参与了Ang II诱导的APP脱落。通过抑制剂gallein阻断G β γ亚基完全阻止了组成性和Ang II诱导的APP脱落。我们的研究结果提供了证据表明，通过Ang II/AT（1）受体刺激诱导APP脱落受G蛋白激活的影响，G β γ亚基起着重要作用。
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.