Amyloid precursor protein mediates proinflammatory activation of monocytic lineage cells

Sondag CM and Combs CK
Source: J Biol Chem
Publication Date: (2004)
Issue: 279(14): 14456-14463
Research Area:
Immunotherapy / Hematology
Cells used in publication:
Species: human
Tissue Origin: blood
Cells of the human monocyte cell line THP-1 were nucleofected with either an individual or a combined pool of siRNA constructs directed against APP. Downregulation of APP levels led to decreased activation/phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and decreased cyclooxygenase-2 (COX-2) protein levels, after cell stimulation by adhesion to collagen. Since p38 MAPK and COX-2 are members of the proinflammatory signaling cascade, these findings provide insight into the contribution of APP to the inflammatory conditions described in Alzheimer's disease.
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.