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.
This study will validate a novel mechanism by which amyloid precursor protein regulates the phenotype of endothelial cells to promote progression of atherosclerotic plaque deposition using a common mouse model of disease. Completion of the study will provide mechanistic understanding of how inhibiting the function of APP in the vasculature will provide an early interventive step in progression of plaque formation by targeting one of the earliest stages of disease, monocyte interaction with the endothelium. This will provide not only a new disease therapy target but also contribute to our understanding of the initial vascular inflammatory components of atherosclerosis.
|Bhatt, Dhaval P; Puig, Kendra L; Gorr, Matthew W et al. (2015) A pilot study to assess effects of long-term inhalation of airborne particulate matter on early Alzheimer-like changes in the mouse brain. PLoS One 10:e0127102|