Amyloid precursor protein mediates a tyrosine kinase-dependent activation response in endothelial cells.
Amyloid precursor protein mediates a tyrosine kinase-dependent activation response in endothelial cells.
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DOI：
10.1523/jneurosci.3107-09.2009
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发表时间：
2009-11-18
期刊：
影响因子：
--
通讯作者：
Combs CK
中科院分区：
文献类型：
--
作者：
Austin SA;Sens MA;Combs CK
淀粉样前体蛋白（APP）是一种广泛表达的I型膜整合蛋白。它具有结合多种细胞外基质成分的能力，并通过其细胞质磷酸酪氨酸682 YENPTY 687结合基序传播信号应答。我们最近证实了在动脉粥样硬化和阿尔茨海默病（AD）组织的脑血管系统中APP、磷酸化APP（Tyr 682）和β-淀粉样蛋白（Aβ）的蛋白水平增加，主要共同定位在内皮层内。这项研究表明，人类和小鼠apoE−/−主动脉的外周血管中存在类似的APP变化，表明APP相关变化并不局限于脑血管。因此，原代小鼠主动脉内皮细胞（PAEC）和人脐静脉内皮细胞（HUVEC）被用作模型系统来研究APP在内皮细胞中的功能。用抗N端APP抗体22 C11进行APP多聚化以模拟配体结合，刺激蛋白磷酸酪氨酸水平、APP磷酸化和Aβ分泌的Src激酶家族依赖性增加。此外，APP多聚化还以Src激酶家族依赖的方式刺激促炎蛋白、环氧合酶（考克斯）-2和VCAM-1的蛋白水平增加。内皮APP也参与介导单核细胞粘附。总的来说，这些数据表明，内皮APP调节免疫细胞粘附和刺激酪氨酸激酶依赖性反应驱动收购的反应性内皮表型。这些APP介导的事件可以作为治疗靶点，用于干预脑血管疾病和AD常见的进行性血管变化。
Amyloid precursor protein (APP) is a ubiquitously expressed type one integral membrane protein. It has the ability to bind numerous extracellular matrix components and propagate signaling responses via its cytoplasmic phosphotyrosine, 682YENPTY687, binding motif. We recently demonstrated increased protein levels of APP, phosphorylated APP (Tyr682), and beta-amyloid (Aβ) in brain vasculature of atherosclerotic and Alzheimer’s disease (AD) tissue co-localizing primarily within the endothelial layer. This study demonstrates similar APP changes in peripheral vasculature from human and mouse apoE−/− aorta suggesting APP-related changes are not restricted to brain vasculature. Therefore, primary mouse aortic endothelial cells (PAEC) and human umbilical vein endothelial cells (HUVEC) were used as a model system to examine the function of APP in endothelial cells. APP multimerization with an anti-N-terminal APP antibody, 22C11, to simulate ligand binding stimulated a Src kinase family dependent increase in protein phosphotyrosine levels, APP phosphorylation, and Aβ secretion. Furthermore, APP multimerization stimulated increased protein levels of the proinflammatory proteins, cyclooxygenase (COX)-2 and vascular cell adhesion molecule (VCAM)-1 also in a Src kinase family dependent fashion. Endothelial APP was also involved in mediating monocytic cell adhesion. Collectively, these data demonstrate that endothelial APP regulates immune cell adhesion and stimulates a tyrosine kinase-dependent response driving acquisition of a reactive endothelial phenotype. These APP-mediated events may serve as therapeutic targets for intervention in progressive vascular changes common to cerebrovascular disease and AD.