Amyloid precursor protein cross‐linking stimulates beta amyloid production and pro‐inflammatory cytokine release in monocytic lineage cells

• Published in: Journal of neurochemistry Vol. 97; no. 2; pp. 449 - 461
• Main Authors: Sondag, C. M., Combs, C. K.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2006; Blackwell
• Subjects: Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - immunology; Amyloid beta-Protein Precursor - pharmacology; amyloid precursor protein; Animals; Antibodies - pharmacology; Biological and medical sciences; Blotting, Western - methods; Cells; Cells, Cultured; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Cerebral Cortex - cytology; cytokine; Cytokines; Cytokines - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Embryo, Mammalian; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay - methods; Fundamental and applied biological sciences. Psychology; Gene Expression - drug effects; Gene Expression - physiology; Humans; Immunohistochemistry - methods; inflammation; L-Lactate Dehydrogenase - metabolism; MAP Kinase Kinase 4 - metabolism; Medical sciences; Mice; microglia; Microglia - drug effects; Microglia - metabolism; Monocytes - drug effects; Monocytes - metabolism; Neurology; Neurosciences; Octoxynol - pharmacology; Peptides; Proteins; RNA, Small Interfering - pharmacology; Surface-Active Agents - pharmacology; Transfection - methods; Vertebrates: nervous system and sense organs; β amyloid; Peptides; Alzheimer disease; Neuroglia; Activation; Integrin; inflammation; Degenerative disease; Alzheimer's disease; β amyloid; Release; Biological receptor; Human; Tyrosine; Nervous system diseases; Monocyte; Rodentia; Attention; Cytokine; Adhesion; Amyloid precursor protein; Cerebral disorder; Microglia; Vertebrata; Mammalia; Mouse; Central nervous system disease
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2006.03759.x

Beta amyloid peptide‐containing neuritic plaques are a defining feature of Alzheimer's disease pathology. Beta amyloid are 38–43 residue peptides derived by proteolytic cleavage of amyloid precursor protein. Although much attention has focused on the proteolytic events leading to beta amyloid generation, the function of amyloid precursor protein remains poorly described. Previously, we reported that amyloid precursor protein functions as a pro‐inflammatory receptor on monocytic lineage cells and defined a role for amyloid precursor protein in adhesion by demonstrating that β1 integrin‐mediated pro‐inflammatory activation of monocytes is amyloid precursor protein dependent. We demonstrated that antibody‐induced cross‐linking of amyloid precursor protein in human THP‐1 monocytes and primary mouse microglia stimulates a tyrosine kinase‐based pro‐inflammatory signaling response leading to acquisition of a reactive phenotype. Here, we have identified pro‐inflammatory mediators released upon amyloid precursor protein‐dependent activation of monocytes and microglia. We show that amyloid precursor protein cross‐linking stimulated tyrosine kinase‐dependent increases in pro‐inflammatory cytokine release and a tyrosine kinase‐independent increase in beta amyloid 1–42 generation. These data provide much needed insight into the function of amyloid precursor protein and provide potential therapeutic targets to limit inflammatory changes associated with the progression of Alzheimer's disease.