Abstract
Alzheimer's disease is a progressive neurodegenerative disorder characterized by extracellular deposition of beta-amyloid (Abeta) peptide containing neuritic plaques. Abeta peptides are proteolytically derived from the membrane-bound amyloid precursor protein (APP). Although the function of APP is not entirely clear, previous studies demonstrate that neuronal APP colocalizes with beta(1) integrin receptors at sites of focal adhesion, suggesting that APP is involved in mediating neuronal process adhesion. Integrin-dependent adhesion is also a well-characterized component of immune cell proinflammatory activation. Using primary mouse microglia and the human monocytic cell line, THP-1, we have begun investigating the role of APP in integrin-dependent activation. Co-immunoprecipitation studies demonstrate that APP is recruited into a multi-receptor signaling complex during beta(1) integrin-mediated adhesion of monocytes. Stimulation induces a subsequent, specific recruitment of tyrosine phosphorylated proteins to APP, including Lyn and Syk. Antibody cross-linking of cell surface APP leads to a similar response characterized by activation and recruitment of tyrosine kinases to APP as well as subsequent activation of mitogen-activated protein kinases and increased proinflammatory protein levels. These data demonstrate that APP can act as a proinflammatory receptor in monocytic lineage cells and provide insight into the contribution of this protein to the inflammatory conditions described in Alzheimer's disease.
Highlights
Amyloid precursor protein (APP)1 is a ubiquitously expressed integral membrane protein from which the 1– 40 and 1– 42 residue -amyloid (A) peptides are proteolytically cleaved [1]
Collagen adhesion stimulated formation of a multi-receptor complex including cell surface amyloid precursor protein (APP) and 1 integrin subunits (Fig. 2C). These data suggest that APP participates in the tyrosine kinase-dependent activation response of 1 integrin receptors in monocytes, those using type I collagen as a ligand
To further define a role for APP in integrin-mediated proinflammatory activation of monocytic lineage cells, we used Small Interference RNA (siRNA) to significantly reduce APP expression (Fig. 5C)
Summary
Amyloid precursor protein (APP) is a ubiquitously expressed integral membrane protein from which the 1– 40 and 1– 42 residue -amyloid (A) peptides are proteolytically cleaved [1]. APP is an integral transmembrane glycoprotein that exists as one of three major splice variants consisting of either 695, 751, or 770 amino acid residues [4] These isoforms are composed of a large glycosylated extracellular region, a single membrane-spanning domain, and a short, highly conserved cytoplasmic tail [1]. The adaptor protein Shc has been identified as an APP-interacting protein; this interaction is promoted by tyrosine phosphorylation of the APP phosphotyrosine-binding motif [10, 11] These data suggest that APP is capable of serving as a docking molecule in membrane proximal signaling events. Inflammatory activation of these cells increases localization of APP to the plasma membrane, suggesting APP participates in adhesion-mediated activation of this cell type [25, 26]. We investigated the role of APP in 1 integrindependent adhesion and activation of the human monocytic cell line, THP-1, and primary mouse microglia
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