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

Ruohan Sun, Tongrong He, Yujun Pan, Zvonimir S Katusic

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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 APPa (sAPPa). 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 sAPPa production by enhancing a disintegrin and metalloprotease (ADAM)10 expression. Furthermore, Ang II impaired expression of ADAM10 and significantly reduced generation of sAPPa in senescent human BMECs. This inhibitory effect of Ang II was prevented by treatment with BACE1 inhibitor IV. Our results suggest that impairment of a-processing and shift to amyloidogenic pathway of APP contribute to endothelial dysfunction induced by senescence. Loss of sAPPa 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.

Original languageEnglish (US)
Pages (from-to)100-114
Number of pages15
JournalAging
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2018

    Fingerprint

Keywords

  • Ang II
  • APP processing
  • BACE1 inhibitor IV
  • Endothelium
  • Senescence

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this