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

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

doi:10.18632/aging.101362

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 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.

Highlights

Epidemiological, experimental and clinical studies have suggested that age-related cerebrovascular dysfunction plays a critical role in the pathogenesis of dementia, including Alzheimer’s disease (AD) [1,2,3,4]
We found that the expression of ADAM10 and ADAM17 were not changed (Figure 2B-C), senescence increased the expression of ADAM9 in passage 15 (P15) human brain microvascular endothelial cells (BMECs) (Figure 2D)
There was no decrease in α-secretase expression, the secretion of soluble APPα (sAPPα) was surprisingly lower in senescent human BMECs (Figure 2E)

Summary

Introduction

Epidemiological, experimental and clinical studies have suggested that age-related cerebrovascular dysfunction plays a critical role in the pathogenesis of dementia, including Alzheimer’s disease (AD) [1,2,3,4]. APP is highly expressed in www.aging‐us.com endothelium and can be processed by two major proteolytic pathways [14]. Amyloidogenic processing of APP sequentially driven by β-site APP cleaving enzyme (BACE1) and γ-secretase generates cytotoxic Aβ [14]. Endothelial APP is primarily processed via nonamyloidogenic pathway [14, 17]. Our previous studies demonstrated that in human brain microvascular endothelial cells (BMECs), ADAM10 is stimulated by activation of prostacyclin (PGI2)/cyclic adenosine monophosphate (cAMP) signaling pathway [16]. We have demonstrated that the expression and activity of BACE1 in cerebrovascular endothelium is suppressed by endothelial nitric oxide synthase (eNOS)/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling [19]. The effects of BACE1 inhibitors on human brain microvascular endothelium have not been defined

Methods

Results

Conclusion