Sun Ruohan, He Tongrong, Pan Yujun, Katusic Zvonimir S
Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, 150001, China.
Department of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Aging (Albany NY). 2018 Jan 15;10(1):100-114. doi: 10.18632/aging.101362.
The present study was designed to determine the effects of senescence and angiotensin II (Ang II) on expression and processing of amyloid precursor protein (APP) in human brain microvascular endothelial cells (BMECs). Senescence caused a decrease in APP expression thereby resulting in reduced secretion of soluble APPα (sAPPα). In contrast, β-site APP cleaving enzyme (BACE1) expression and production of amyloid β (Aβ)40 were increased in senescent endothelium. Importantly, in senescent human BMECs, treatment with BACE1 inhibitor IV inhibited Aβ generation and increased sAPPα production by enhancing a disintegrin and metalloprotease (ADAM)10 expression. Furthermore, Ang II impaired expression of ADAM10 and significantly reduced generation of sAPPα in senescent human BMECs. This inhibitory effect of Ang II was prevented by treatment with BACE1 inhibitor IV. Our results suggest that impairment of α-processing and shift to amyloidogenic pathway of APP contribute to endothelial dysfunction induced by senescence. Loss of sAPPα in senescent cells treated with Ang II exacerbates detrimental effects of senescence on APP processing. Notably, inhibition of BACE1 has beneficial effects on senescence induced endothelial dysfunction. Reported findings may help to explain contributions of senescent cerebral microvascular endothelium to development of cerebral amyloid angiopathy and Alzheimer's disease (AD) pathology.
本研究旨在确定衰老和血管紧张素II（Ang II）对人脑微血管内皮细胞（BMECs）中淀粉样前体蛋白（APP）表达和加工的影响。衰老导致APP表达下降，从而使可溶性APPα（sAPPα）的分泌减少。相反，衰老内皮细胞中β位点APP裂解酶（BACE1）的表达和淀粉样β（Aβ）40的产生增加。重要的是，在衰老的人BMECs中，用BACE1抑制剂IV处理可抑制Aβ生成，并通过增强解整合素和金属蛋白酶（ADAM）10的表达来增加sAPPα的产生。此外，Ang II损害衰老的人BMECs中ADAM10的表达，并显著减少sAPPα的产生。BACE1抑制剂IV处理可阻止Ang II的这种抑制作用。我们的结果表明，APP的α加工受损和向淀粉样生成途径的转变导致衰老诱导的内皮功能障碍。用Ang II处理的衰老细胞中sAPPα的丧失加剧了衰老对APP加工的有害影响。值得注意的是，抑制BACE1对衰老诱导的内皮功能障碍具有有益作用。报道的研究结果可能有助于解释衰老的脑微血管内皮细胞对脑淀粉样血管病和阿尔茨海默病（AD）病理发展的贡献。
