Research Paper Volume 10, Issue 1 pp 100—114

Effects of senescence and angiotensin II on expression and processing of amyloid precursor protein in human cerebral microvascular endothelial cells

Ruohan Sun1,2, , Tongrong He2, , Yujun Pan1, , Zvonimir S. Katusic2, ,

  • 1 Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, 150001, China
  • 2 Department of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA

Received: September 15, 2017       Accepted: January 10, 2018       Published: January 15, 2018
How to Cite

Copyright: Sun et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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.


Aβ: amyloid β; AD: Alzheimer’s disease; ADAM: a disintegrin and metalloprotease; Ang II: angiotensin II; APP: amyloid precursor protein; AT1R: angiotensin II type 1 receptor; AT2R: angiotensin II type 2 receptor; BACE1: β-site APP cleaving enzyme 1; BACE1 inhibitor IV: β-secretase inhibitor IV; BMECs: brain microvascular endothelial cells; cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; EBM2: endothelial basal medium 2; EGM2: endothelial growth medium 2; eNOS: endothelial nitric oxide synthase; NF-κB: nuclear factor κB; NO: nitric oxide; P5: passage 5; P15: passage 15; PGI2: prostacyclin; PKC: protein kinase C; SA-β-Gal: senescence-associated β-galactosidase; sAPPα: soluble APPα.