The Role of APP in Atheroclerosis

描述（由申请人提供）：单核细胞-内皮相互作用被认为是动脉粥样硬化过程中的早期事件。因此，通过反应性血管内皮限制单核细胞粘附或渗出的策略在早期应该是有效的。这与目前试图调节脂质代谢或血栓形成的治疗努力不同。我们的初步数据表明，淀粉样蛋白前体蛋白（APP）是内皮细胞和单核细胞上针对早期动脉粥样硬化的合适蛋白。虽然APP经常被描述为与阿尔茨海默病（AD）有关，但在一系列病理过程中，它在多种细胞类型中上调。我们观察到动脉粥样硬化的人和小鼠的主动脉和大脑内皮上调APP的表达，它似乎介导了内皮细胞中特定的酪氨酸激酶激活反应，调节了它们的激活和随后的单核细胞粘附。这些数据表明，APP有助于炎症内皮的单核细胞粘附，从而导致外周血管和脑血管的动脉粥样硬化斑块形成。这是该蛋白的一种新功能，意味着它可能是老年疾病阶段治疗干预的目标。我们将通过首先证明APP是高脂肪死亡依赖性动脉粥样硬化斑块形成和血管炎症所必需的，使用常见的动脉粥样硬化小鼠模型，apoE-/-小鼠，与没有APP的小鼠杂交（APP-/-）来验证这一观点。接下来，我们将使用内皮细胞和单核细胞的原代培养来证明特定的、app依赖的相互作用以及在细胞-细胞相互作用过程中调节的随后的表型变化。确定APP在动脉粥样硬化斑块形成中的作用是本研究的一个创新组成部分。这项工作的影响不仅将确定一种新的疾病机制并为APP提供功能，而且还将刺激我们的团队和其他人为未来的治疗开发APP抑制剂策略。我们也期望APP在调节免疫细胞和血管行为方面的作用最终与AD的机制直接相关。

DESCRIPTION (provided by applicant): Monocyte-endothelial interaction is presumed to be an early event in the atherosclerotic process. Therefore, a strategy to limit monocyte adhesion or diapedesis through reactive vessel endothelium should be effective at this early stage. This is a departure from current therapeutic efforts that attempt to modulate lipid metabolism or thrombus formation. Our preliminary data demonstrates that amyloid precursor protein (APP) is an appropriate protein on endothelial cells and monocytes for targeting early stage atherosclerosis. Although APP is often described in relation to Alzheimer's disease (AD), it is upregulated in a variety of cell types during a range of pathologies. We observed that atherosclerotic human and mouse endothelium in both aorta and brain upregulate APP expression where it appears to mediate a specific tyrosine kinase-based activation response in endothelial cells that regulates their activation and subsequent monocytic adhesion. These data suggest that APP contributes to monocyte adhesion in inflamed endothelium which can lead to atherosclerotic plaque formation in both peripheral and cerebral vasculature. This is a novel function for this protein implicating it as a possible target for therapeutic intervention during erly disease stages. We will test this idea by first demonstrating that APP is required for high-fat die dependent atherosclerotic plaque formation and vessel inflammation using the common murine model of atherosclerosis, apoE-/- mice, crossed to mice without APP (APP-/-). We will next use primary cultures of endothelial cells and monocytes to demonstrate the specific, APP-dependent interactions and subsequent phenotype changes that are regulated during cell-cell interaction. Defining a role for APP in atherosclerotic plaque formation represents an innovative component of this study. The impact from this work will not only identify a new disease mechanism and provide a function for APP but will also stimulate our group and others to develop APP inhibitor strategies for future therapeutics. We also expect this role of APP in regulating immune cell and vessel behavior will ultimately be directly relevant to mechanisms of AD.