Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels

Abstract

We tested hypothesis that activation of the prostacyclin (PGI 2 ) receptor (IP receptor) signaling pathway in cerebral microvessels plays an important role in the metabolism of amyloid precursor protein (APP). In human brain microvascular endothelial cells activation of IP receptor with the stable analogue of PGI 2 , iloprost, stimulated expression of amyloid precursor protein and a disintegrin and metalloprotease 10 (ADAM10), resulting in an increased production of the neuroprotective and anticoagulant molecule, soluble APPa (sAPPa). Selective agonist of IP receptor, cicaprost, and adenylyl cyclase activator, forskolin, also enhanced expression of amyloid precursor protein and ADAM10. Notably, in cerebral microvessels of IP receptor knockout mice, protein levels of APP and ADAM10 were reduced. In addition, iloprost increased protein levels of peroxisome proliferator-activated receptor d (PPARd) in human brain microvascular endothelial cells. PPARd-siRNA abolished iloprost-augmented protein expression of ADAM10. In contrast, GW501516 (a selective agonist of PPARd) upregulated ADAM10 and increased production of sAPPa. Genetic deletion of endothelial PPARd (ePPARd À/À ) in mice significantly reduced cerebral microvascular expression of ADAM10 and production of sAPPa. In vivo treatment with GW501516 increased sAPPa content in hippocampus of wild type mice but not in hippocampus of ePPARd À/À mice. Our findings identified previously unrecognized role of IP-PPARd signal transduction pathway in the production of sAPPa in cerebral microvasculature.

Expression and Processing of Amyloid Precursor Protein in Vascular Endothelium

“…The amyloidogenic processing pathway is unaffected by PGI 2 in brain microvessel endothelial cells (Table 1). Furthermore, deletion of PPAR␦ abolished the iloprost-induced ADAM10 activation and release of sAPP␣ in brain microvessel endothelial cells, thus demonstrating that PGI 2induced generation of sAPP␣ is also dependent on activation of PPAR␦ (78).…”

“…Several isoforms of a disintegrin and metalloproteinase (ADAM) are responsible for ␣-secretase activity: ADAM9, ADAM10, and ADAM17. In human cerebrovascular endothelium, ADAM10 (but not ADAM9 or ADAM17) appears to be the most relevant constitutively active ␣-secretase, even though all three isoforms are expressed in endothelial cells (78,100).…”

“…Thus sAPP␣ released from platelets may function in both cerebral and peripheral vascular system as an anticoagulant and hence makes an important contribution to the regulation of hemostasis (35,105,164,165). Production and release of sAPP␣ from endothelium also contributes to protection against coagulation (see below) (31,78,157).…”

Prostacyclin Promotes Degenerative Pathology in a Model of Alzheimer’s disease

“…These findings are supported by recent work on prostacyclin signaling influencing APP processing mechanisms. Agonist activation of the IP receptor was found to increase the expression of the amyloid precursor protein, resulting in the increased production of Aβ (49). Another report suggests that downstream activation of the PKA/CREB pathway after prostacyclin injections induces upregulation of γ-secretase cleaving enzymes and leads to an accumulation of Aβ c-terminal fragments in an APP/PS1 transgenic mouse model (50).…”

“…Several studies have suggested that PGI2 may have some impact on neurodegenerative disorders such as Alzheimer's disease (47,48). He et al (49) was able to show that agonist-induced activation of the IP receptor-stimulated production of soluble APPα, a neuroprotective isoform of the amyloid precursor protein, in isolated human microvascular endothelial cells. Wang et al (50) demonstrated that injections of PGI2 into an amyloid precursor protein/presenilin 1 transgenic mouse model increased Aβ levels and proposed this was due to upregulation of the amyloid cleaving proteins, γ-secretase APH1α, and APH1β, via the PKA/CREB and JNK/c-Jun pathways.…”