Amyloid precursor protein 770 is specifically expressed and released from platelets

Abstract

Platelets not only play an essential role in hemostasis after vascular injury but are also involved in the development of coronary artery disease (CAD) and cerebrovascular lesions. Patients with CAD and cerebral ischemia are recommended to undergo antiplatelet therapy, but they have an increased incidence of major bleeding complications. Both assessment of the platelet activation status and response to antiplatelet therapy in each patient are highly desired. β-Amyloid precursor protein (APP) 770 is expressed in vascular endothelial cells, and its extracellular region, a soluble form of APP770 (sAPP770, also called nexin-2), is proteolytically cleaved for shedding. Abundant sAPP770 is also released from activated platelets. In this study, we used peripheral blood samples from patients with CAD and control subjects and evaluated sAPP770 as a specific biomarker for platelet activation. First, the plasma levels of sAPP770 correlated well with those of the soluble form CD40 ligand (CD40L), an established biomarker for platelet activation. Additionally, flow cytometry analysis using peripheral blood cells showed that CD40L expression is up-regulated in activated T cells, whereas APP770 expression is negligible in all blood cell types except platelets. Following stimulation with collagen or ADP, aggregating platelets immediately released sAPP770. Finally, patients with dual antiplatelet therapy showed significantly lower levels of plasma sAPP770 than those with no therapy. Taken together, our data show that plasma sAPP770 could be a promising biomarker for platelet activation. Platelets not only play an essential role in hemostasis after vascular injury but are also involved in the development of coronary artery disease (CAD) and cerebrovascular lesions. Patients with CAD and cerebral ischemia are recommended to undergo antiplatelet therapy, but they have an increased incidence of major bleeding complications. Both assessment of the platelet activation status and response to antiplatelet therapy in each patient are highly desired. β-Amyloid precursor protein (APP) 770 is expressed in vascular endothelial cells, and its extracellular region, a soluble form of APP770 (sAPP770, also called nexin-2), is proteolytically cleaved for shedding. Abundant sAPP770 is also released from activated platelets. In this study, we used peripheral blood samples from patients with CAD and control subjects and evaluated sAPP770 as a specific biomarker for platelet activation. First, the plasma levels of sAPP770 correlated well with those of the soluble form CD40 ligand (CD40L), an established biomarker for platelet activation. Additionally, flow cytometry analysis using peripheral blood cells showed that CD40L expression is up-regulated in activated T cells, whereas APP770 expression is negligible in all blood cell types except platelets. Following stimulation with collagen or ADP, aggregating platelets immediately released sAPP770. Finally, patients with dual antiplatelet therapy showed significantly lower levels of plasma sAPP770 than those with no therapy. Taken together, our data show that plasma sAPP770 could be a promising biomarker for platelet activation. The primary function of platelets is to stop hemorrhage after vascular injury, but recent accumulating reports have revealed their important role in the development of atherosclerotic lesions (1Davì G. Patrono C. Platelet activation and atherothrombosis.N. Engl. J. Med. 2007; 357 (18077812): 2482-249410.1056/NEJMra071014Crossref PubMed Scopus (1718) Google Scholar, 2Ruggeri Z.M. Platelets in atherothrombosis.Nat. Med. 2002; 8 (12411949): 1227-123410.1038/nm1102-1227Crossref PubMed Scopus (1363) Google Scholar). Rupture of these lesions triggers the acute onset of arterial thrombosis, which could lead to acute coronary syndrome (ACS) and ischemic stroke. Various antiplatelet drugs have been developed to treat and prevent atherothrombosis (3Patrono C. Coller B. FitzGerald G.A. Hirsh J. Roth G. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126 (15383474): 234S-264S10.1378/chest.126.3_suppl.234SAbstract Full Text Full Text PDF PubMed Scopus (618) Google Scholar). Low-dose aspirin inhibits platelet cyclooxygenase-1, thereby reducing the synthesis of thromboxane A2, a platelet activator. Thienopyridine, an antagonist of P2Y12, which is a major ADP receptor on platelets, inhibits ADP-induced platelet activation. In the 1990s, dual antiplatelet therapy (DAPT; aspirin plus a P2Y12 inhibitor) was shown to reduce the incidence of stent thrombosis after percutaneous interventions (4Leon M.B. Baim D.S. Popma J.J. Gordon P.C. Cutlip D.E. Ho K.K. Giambartolomei A. Diver D.J. Lasorda D.M. Williams D.O. Pocock S.J. Kuntz R.E. Stent Anticoagulation Restenosis Study InvestigatorsA clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting.N. Engl. J. Med. 1998; 339 (9834303): 1665-167110.1056/NEJM199812033392303Crossref PubMed Scopus (1683) Google Scholar). Conversely, antiplatelet therapy increases the incidence of major bleeding complications (mostly in the upper gastrointestinal tract) (3Patrono C. Coller B. FitzGerald G.A. Hirsh J. Roth G. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126 (15383474): 234S-264S10.1378/chest.126.3_suppl.234SAbstract Full Text Full Text PDF PubMed Scopus (618) Google Scholar). How to set up the duration of DAPT in coronary artery disease (CAD) patients remains unclear. Although the ex vivo measurement of platelet responsiveness to various agonists can evaluate the function of platelets, such measurements show no correlation with platelet activation in vivo (1Davì G. Patrono C. Platelet activation and atherothrombosis.N. Engl. J. Med. 2007; 357 (18077812): 2482-249410.1056/NEJMra071014Crossref PubMed Scopus (1718) Google Scholar). Activated platelets lead to the release of granular components and relocalization of membrane proteins to the cell surface. Upon platelet activation, surface P-selectin is expressed on the platelet membrane (5Larsen E. Celi A. Gilbert G.E. 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However, no practical biomarker is available to evaluate platelet activation. Amyloid precursor protein (APP) is a membrane protein that generates β-amyloid (Aβ) peptide, and the accumulation of Aβ and neurofibrillary tangles in the brain triggers the onset of Alzheimer's disease (16Selkoe D.J. Alzheimer's disease: genes, proteins, and therapy.Physiol. Rev. 2001; 81 (11274343): 741-76610.1152/physrev.2001.81.2.741Crossref PubMed Scopus (5162) Google Scholar, 17De Strooper B. Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process.Physiol. Rev. 2010; 90 (20393191): 465-49410.1152/physrev.00023.2009Crossref PubMed Scopus (351) Google Scholar). APP has three kinds of alternatively spliced mRNA isoforms: APP695, APP751, and APP770 (18Ponte P. Gonzalez-DeWhitt P. Schilling J. Miller J. Hsu D. Greenberg B. Davis K. Wallace W. Lieberburg I. Fuller F. A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors.Nature. 1988; 331 (2893289): 525-52710.1038/331525a0Crossref PubMed Scopus (860) Google Scholar, 19Tanzi R.E. McClatchey A.I. Lamperti E.D. Villa-Komaroff L. Gusella J.F. Neve R.L. Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease.Nature. 1988; 331 (2893290): 528-53010.1038/331528a0Crossref PubMed Scopus (873) Google Scholar). APP695 is predominantly expressed in neurons (20Wertkin A.M. Turner R.S. Pleasure S.J. Golde T.E. Younkin S.G. Trojanowski J.Q. Lee V.M. Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular β-amyloid or A4 peptides.Proc. Natl. Acad. Sci. U.S.A. 1993; 90 (8415732): 9513-951710.1073/pnas.90.20.9513Crossref PubMed Scopus (195) Google Scholar), whereas APP770 is found in vascular endothelial cells (21Kitazume S. Tachida Y. Kato M. Yamaguchi Y. Honda T. Hashimoto Y. Wada Y. Saito T. N. T. N. endothelial cells produce amyloid from amyloid precursor protein 770 and the 2010; Full Text Full Text PDF PubMed Scopus Google Scholar) and platelets A.I. B. R. Fuller S. E. J. D. A. P. amyloid precursor protein of Alzheimer's disease is released by human Full Text PDF PubMed Google Scholar). The soluble form of APP770 is released platelet activation, and plasma sAPP770 levels are significantly in patients S. A. T. M. Tachida Y. K. R. Y. N. Y. K. N. H. N. T. amyloid precursor protein 770 is released from endothelial cells and activated a biomarker for acute coronary Full Text Full Text PDF PubMed Scopus Google Scholar). In this study, by blood samples from control subjects and CAD we found a correlation the plasma levels of sAPP770 and sCD40L and that APP770 expression is to platelets in blood with those in control subjects and CAD patients with aspirin the plasma sAPP770 levels significantly lower in CAD patients with the that plasma sAPP770 can be a platelet activation a of APP770 using and plasma and found that the and to those of plasma and as in the data sCD40L is an established laboratory marker for platelet activation, we the of plasma sAPP770 with that of The plasma samples from healthy or and used to sCD40L and sAPP770 levels using The plasma sAPP770 was whereas the plasma sCD40L was lower of plasma samples showed sCD40L levels is that CAD patients have levels of sCD40L (13Aukrust P. Müller F. Ueland T. Berget T. Aaser E. Brunsvig A. Solum N.O. Forfang K. Frøland S.S. Gullestad L. Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina: possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes.Circulation. 1999; 100 (10441098): 614-62010.1161/01.cir.100.6.614Crossref PubMed Scopus (482) Google Scholar) and sAPP770 S. A. T. M. Tachida Y. K. R. Y. N. Y. K. N. H. N. T. amyloid precursor protein 770 is released from endothelial cells and activated a biomarker for acute coronary Full Text Full Text PDF PubMed Scopus Google Scholar), we plasma from CAD patients and control such as and of samples from CAD patients and of samples from control subjects show sCD40L and the samples used to sAPP770 found a correlation the sAPP770 and sCD40L levels the of sAPP770 as a promising biomarker for platelet activation. human peripheral blood cell types than platelets express APP770 or APP this we used and the of which all APP In cells, which cells, APP770 expression was not whereas the APP was from peripheral blood cells and found that of the APP in T and cells and also a to that APP770 expression is to platelets. blood cells by we for which is expressed levels on all cells of except and platelets. the of we blood cells with with T and Both APP and APP770 in these cell types plasma we also platelets, which showed for platelet markers such as and and found that the platelets expressed T cells show CD40L is that CD40L surface expression is in activated T cells (7Armitage R.J. Fanslow W.C. Strockbine L. Sato T.A. Clifford K.N. Macduff B.M. Anderson D.M. Gimpel S.D. Davis-Smith T. Maliszewski C.R. Molecular and biological characterization of a murine ligand for CD40.Nature. 1992; 357 (1374165): 80-8210.1038/357080a0Crossref PubMed Scopus (983) Google Scholar, B. V. D. Kroczek R.A. and function of soluble TRAP (CD40 ligand) interaction of primary T cells with J. Immunol. PubMed Scopus Google Scholar). activated could APP770 found that T cells activated with and showed cell surface CD40L whereas activated not express levels of surface APP770 expression The APP with the inhibitor has been as a membrane protein and protein in platelets A.I. B. R. Fuller S. E. J. D. A. P. amyloid precursor protein of Alzheimer's disease is released by human Full Text PDF PubMed Google Scholar, J.S. D.D. Protease a platelet PubMed Scopus Google Scholar). intracellular of membrane-bound APP remains unclear. we surface APP770 expression is found in platelets and after activation. platelets showed APP770 expression platelet activation, as by with which activated surface APP770 expression not but the of platelets was The that membrane relocalization platelet activation the surface APP770 platelets with the collagen or ADP and sAPP770 Both agonists the release of sAPP770 platelet and levels of ADP to a platelet that was of by a of and the of sAPP770 was The that the of is for the sAPP770 levels of sAPP770 released from platelets, we the and of and platelet activation with the Although and found to be released from platelets, was and The sAPP770 than the of plus could be by the samples used in the and which of the APP770 the of platelet APP stimulation in we analysis using APP and APP the of M. S. M. S. D. S. A. H. Müller V. C. B. A. of APP inhibits in the PubMed Scopus Google Scholar). platelet activation, a to APP was in response to sAPP770 Although we observed a major to by an of blood sAPP770 is a biomarker for platelet activation, we the blood sAPP770 of blood samples from healthy human showed that the sAPP770 was in in and in is considered that of endothelial APP770 in the release of sAPP770 S. A. T. M. Tachida Y. K. R. Y. N. Y. K. N. H. N. T. amyloid precursor protein 770 is released from endothelial cells and activated a biomarker for acute coronary Full Text Full Text PDF PubMed Scopus Google Scholar) and increased plasma sAPP770. The sAPP770 levels than plasma sAPP770 are to platelets activated and in to release sAPP770. we that platelets are unstable in blood and activated platelets to the increased sAPP770 this we and blood samples for up to and plasma the the sAPP770 levels in but sAPP770 was observed in with the the of the blood sAPP770 levels the found that sAPP770 levels not the However, plasma sAPP770 levels but not in the which could be to the a in the of onset of with a from to C. E. R. T. in the of onset of acute myocardial Engl. J. Med. PubMed Scopus Google Scholar). that plasma sAPP770 levels be by antiplatelet therapy. the sAPP770 levels in plasma are by the the and the we to sAPP770 levels in plasma samples in control subjects with CAD antiplatelet therapy, CAD patients with aspirin and CAD patients with found that the levels of plasma sAPP770 in CAD patients with DAPT significantly lower than those of control subjects therapy The that blood levels of sAPP770 are by the of antiplatelet therapy, and we that plasma sAPP770 could be a promising marker for platelet in CAD In this study, we show that APP770 is expressed in platelets but in peripheral blood platelets are in peripheral we to platelets from blood cell APP770 is detected in blood cell cytometry analysis of platelets showed surface APP770 whereas detected levels of released and platelet activation. In our using APP and APP770 membrane-bound APP for than of APP in platelets S. A. T. M. Tachida Y. K. R. Y. N. Y. K. N. H. N. T. amyloid precursor protein 770 is released from endothelial cells and activated a biomarker for acute coronary Full Text Full Text PDF PubMed Scopus Google Scholar). APP has by and and which Aβ by C. C. G. S. and of Med. PubMed Scopus Google Scholar, G. Amyloid precursor protein and Full Text Full Text PDF PubMed Scopus Google Scholar). analysis using showed that a of APP platelet activation. Both and have been in platelets K. F. Platelet amyloid precursor protein a for Alzheimer's Sci. Full Text Full Text PDF PubMed Scopus Google Scholar), that sAPP770 could be from membrane-bound APP770 in platelets. A recent using analysis showed that plasma Aβ is a marker for Alzheimer's disease A. N. Kato T. J. V. C. R. C. T. K. K. K. Y. plasma for Alzheimer's disease.Nature. PubMed Scopus Google Scholar). to our that levels of and are released from platelets, was is that levels of and Aβ are detected in the of endothelial cells (21Kitazume S. Tachida Y. Kato M. Yamaguchi Y. Honda T. Hashimoto Y. Wada Y. Saito T. N. T. N. endothelial cells produce amyloid from amyloid precursor protein 770 and the 2010; Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. T. M. Tachida Y. K. R. Y. N. Y. K. N. H. N. T. amyloid precursor protein 770 is released from endothelial cells and activated a biomarker for acute coronary Full Text Full Text PDF PubMed Scopus Google Scholar). be or significantly in platelets. is the functional role of platelet sAPP770 is a inhibitor of R.A. Wagner R. Protease protein a inhibitor of Clin. Invest. 1993; PubMed Scopus Google Scholar) and the inhibition of by 1995; Full Text PDF PubMed Scopus Google Scholar). of sAPP770 have been in sAPP770 in platelets in vivo cerebral thrombosis and increases hemorrhage F. M.L. of hemorrhage in mice cerebral 2007; 38 PubMed Scopus Google Scholar). In our study, patients levels of plasma sAPP770 than with control subjects S. A. T. M. Tachida Y. K. R. Y. N. Y. K. N. H. N. T. amyloid precursor protein 770 is released from endothelial cells and activated a biomarker for acute coronary Full Text Full Text PDF PubMed Scopus Google Scholar). Although patients with antiplatelet therapy have lower levels of plasma sAPP770 than those of control our has of the In the study, control subjects considered from CAD or thrombosis, and they no antiplatelet therapy. all CAD patients antiplatelet therapy by their they our plasma samples from CAD patients antiplatelet therapy plasma samples of antiplatelet therapy we found that CAD patients with DAPT lower levels of plasma sAPP770 than control subjects therapy. plasma sAPP770 could be a promising marker for platelet the platelet response to antiplatelet therapy, the has been used A. A. M. A. K. D. E. D. V. platelet inhibition after with the the thrombosis risk assessment 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, W. J.Y. Low-dose aspirin increases aspirin in patients with coronary artery J. Med. Full Text Full Text PDF PubMed Scopus Google Scholar). is a that platelet ex the function of platelets could be Although plasma sAPP770 levels the platelet activation status in such as and thrombosis, such be by is by and levels J.J. T.J. D.J. of on the of platelet function the and platelet PubMed Scopus Google Scholar, A.M. The of the to antiplatelet a of the PubMed Scopus Google Scholar, D. D. R. M. W. P.C. M. of aspirin using the platelet function J. Cardiol. Full Text Full Text PDF PubMed Scopus Google Scholar), and these are of CAD plasma sAPP770 levels are by these A using the platelet activation status and or duration of antiplatelet therapy in each Human by the of and by the of Human blood samples from healthy CAD and control subjects CAD patients as those percutaneous and aspirin or whereas control subjects and no of CAD antiplatelet therapy. The used in this as from inhibitor from protein from APP770 from cell stimulation from all from or The available used and and and and from The for human CD40L APP770 and used to the human human blood samples using 25 for and for or blood samples using or and for of The was for Human peripheral from human blood samples using to the in in and activated with the cell stimulation for human of was of lymphocyte in a samples with and for 25 after which the lower was samples from healthy on the of the using was by for and platelets from the by for in the of The platelet was in to a of of or platelets used for platelet which in with in a Platelet was by collagen or or ADP or each the or platelet for and the used to the levels of and by The cells, as in and in with the primary for the cells with the primary for by with the for The cells by flow cytometry using a of the primary and are in Human blood using for 25 to and blood The was in and to platelets, and the was was of the blood cell by for 25 the but not and platelets, using was blood cell and was for 25 The with and to cells, and T cells, The cell of using and to the of the platelet and after activation using a and was in the in for with in the with the primary by with the was used to the The of the protein using an of the primary and are in using data are the and and for the of APP770 with coronary artery disease amyloid precursor protein acute coronary syndrome dual antiplatelet therapy CD40 ligand soluble form β-amyloid plasma

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