Soluble amyloid precursor protein 770 is released from inflamed endothelial cells and activated platelets: a novel biomarker for acute coronary syndrome.
ABSTRACT Most Alzheimer disease (AD) patients show deposition of amyloid β (Aβ) peptide in blood vessels as well as the brain parenchyma. We previously found that vascular endothelial cells express amyloid β precursor protein (APP) 770, a different APP isoform from neuronal APP695, and produce Aβ. Since the soluble APP cleavage product, sAPP, is considered to be a possible marker for AD diagnosis, sAPP has been widely measured as a mixture of these variants. We hypothesized that measurement of the endothelial APP770 cleavage product in patients separately from that of neuronal APP695 would enable discrimination between endothelial and neurological dysfunctions. Using our newly developed ELISA system for sAPP770, we observed that inflammatory cytokines significantly enhanced sAPP770 secretion by endothelial cells. Furthermore, we unexpectedly found that sAPP770 was rapidly released from activated platelets. We also found that cerebrospinal fluid mainly contained sAPP695, while serum mostly contained sAPP770. Finally, to test our hypothesis that sAPP770 could be an indicator for endothelial dysfunction, we applied our APP770 ELISA to patients with acute coronary syndrome (ACS), in which endothelial injury and platelet activation lead to fibrous plaque disruption and thrombus formation. Development of a biomarker is essential to facilitate ACS diagnosis in clinical practice. The results revealed that ACS patients had significantly higher plasma sAPP770 levels. Furthermore, in myocardial infarction model rats, an increase in plasma sAPP preceded the release of cardiac enzymes, currently used markers for acute myocardial infarction. These findings raise the possibility that sAPP770 can be a useful biomarker for ACS.
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ABSTRACT: Amyloid Precursor Protein (APP) is a type I membrane protein that undergoes extensive processing by secretases, including BACE1. Although mutations in APP and genes that regulate processing of APP, such as PSENs and BRI2/ITM2B, cause dementias, the normal function of APP in synaptic transmission, synaptic plasticity and memory formation is poorly understood. To grasp the biochemical mechanisms underlying the function of APP in the central nervous system, it is important to first define the sub-cellular localization of APP in synapses and the synaptic interactome of APP. Using biochemical and electron microscopy approaches, we have found that APP is localized in pre-synaptic vesicles, where it is processed by Bace1. By means of a proteomic approach, we have characterized the synaptic interactome of the APP intracellular domain. We focused on this region of APP because in vivo data underline the central funtional and pathological role of the intracellular domain of APP. Consistent with the expression of APP in pre-synaptic vesicles, the synaptic APP intracellular domain interactome is predominantly constituted by pre-synaptic, rather than post-synaptic, proteins. This pre-synaptic interactome of the APP intracellular domain includes proteins expressed on pre-synaptic vesicles such as the vesicular SNARE Vamp2/Vamp1 and the Ca2+ sensors Synaptotagmin-1/Synaptotagmin-2, and non-vesicular pre-synaptic proteins that regulate exocytosis, endocytosis and recycling of pre-synaptic vesicles, such as target-membrane-SNAREs (Syntaxin-1b, Syntaxin-1a, Snap25 and Snap47), Munc-18, Nsf, α/β/γ-Snaps and complexin. These data are consistent with a functional role for APP, via its carboxyl-terminal domain, in exocytosis, endocytosis and/or recycling of pre-synaptic vesicles.PLoS ONE 09/2014; 9(9):e108576. · 3.53 Impact Factor
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ABSTRACT: En este artículo se revisan los biomarcadores no troponínicos con posibles sensibilidad y selectividad, que aportan una perspectiva diagnóstica en el síndrome coronario agudo, y su posible uso en los algoritmos de estratificación del riesgo. Dichos biomarcadores pueden ser útiles como análisis complementarios o alternativos a los de troponina cardiaca (I o T) en el diagnóstico precoz del síndrome coronario agudo, así como para monitorizar su progresión y evaluar el pronóstico. La información presentada en este artículo se basa en un análisis crítico de una selección de la literatura biomédica disponible a través de los motores de búsqueda Scopus y MEDLINE-PubMed de la National Library of Medicine de Estados Unidos. La mayor parte de los artículos citados en este trabajo de revisión y perspectiva, excepto unas pocas publicaciones históricas de referencia, se publicó entre enero de 2000 y diciembre de 2013.Revista Espa de Cardiologia 04/2014; · 3.20 Impact Factor
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ABSTRACT: Soluble fragments of the amyloid precursor protein (APP) generated by alpha- and beta-secretases, sAPPalpha and sAPPbeta, have been postulated as promising new cerebrospinal fluid (CSF) biomarkers for the clinical diagnosis of Alzheimer's disease (AD). However, the capacity of these soluble proteins to assemble has not been explored and could be relevant. Our aim is to characterize possible sAPP oligomers that could contribute to the quantification of sAPPalpha and sAPPbeta in CSF by ELISA, as well as to characterize the possible presence of soluble full-length APP (sAPPf). We employed co-immunoprecipitation, native polyacrylamide gel electrophoresis and ultracentrifugation in sucrose density gradients to characterize sAPP oligomers in CSF. We have characterized the presence of sAPPf in CSF from NDC and AD subjects and demonstrated that all forms, including sAPPalpha and sAPPbeta, are capable of assembling into heteromers, which differ from brain APP membrane-dimers. We measured sAPPf, sAPPalpha and sAPPbeta by ELISA in CSF samples from AD (n = 13) and non-disease subjects (NDC, n = 13) before and after immunoprecipitation with antibodies against the C-terminal APP or against sAPPbeta. We demonstrated that these sAPP heteromers participate in the quantification of sAPPalpha and sAPPbeta by ELISA. Immunoprecipitation with a C-terminal antibody to remove sAPPf reduced by ~30% the determinations of sAPPalpha and sAPPbeta by ELISA, whereas immunoprecipitation with an APPbeta antibody reduced by ~80% the determination of sAPPf and sAPPalpha. The presence of sAPPf and sAPP heteromers should be taken into consideration when exploring the levels of sAPPalpha and sAPPbeta as potential CSF biomarkers.Molecular Neurodegeneration 01/2015; 10(1):2. · 5.29 Impact Factor