Date of Award
4-19-2010
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biology
First Advisor
Colin K. Combs
Abstract
Amyloid precursor protein (APP) is a ubiquitously expressed type one integral membrane protein. Due to its ability to bind components of the extracellular matrix and propagate signaling responses via its cytoplasmic phosphotyrosine binding motif it has been suggested to function in cellular adhesion. Here, we utilized brain tissue and aorta from human and apolipoprotein E -/- (apoE-/-) mice to examine vascular inflammation associated changes related to APP. We also examined AD brain tissue for similar changes. Human atherosclerotic aorta, human AD cerebrovasculature and mouse apoE-/- aorta and cerebrovasculature revealed strong endothelial immunoreactivity for APP, APP phosphorylated at tyrosine residue 682 (pAPP) and Aβ. Furthermore, there was increased APP association with the tyrosine kinase, Src in both diseased brain tissues. Lastly, utilizing a modified Stamper-Woodruff adhesion assay, we demonstrated that adhesion of monocytic cells to apoE -/- and AD brain endothelium is at least partially APP-dependent. These data suggest similar endothelial changes between these two diseases. 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, vascular cell adhesion molecule (VCAM)-1 and inducible nitricoxide synthase (iNOS) 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.
Recommended Citation
Austin, Susan A., "APP Is A Novel Proinflammatory Receptor On Vascular Endothelium That Is Involved In The Vascular Dysfunction Associated With Atherosclerosis And AD" (2010). Theses and Dissertations. 8058.
https://commons.und.edu/theses/8058