Amyloid-β Peptide-Receptor for Advanced Glycation Endproduct Interaction Elicits Neuronal Expression of Macrophage-Colony Stimulating Factor: A Proinflammatory Pathway in Alzheimer Disease

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 94; no. 10; pp. 5296 - 5301
• Main Authors: Du Yan, Shi, Zhu, Huaijie, Fu, Jin, Yan, Shi Fang, Roher, Alex, Tourtellotte, Wallace W., Rajavashisth, Tripathi, Chen, Xi, Godman, Gabriel C., Stern, David, Schmidt, Ann Marie
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 13.05.1997; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences of the USA
• Subjects: Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - pharmacology; Anger; Animals; Antigens; Biological Sciences; Brain; Cells, Cultured; Cerebrospinal fluid; Chemotaxis; Gels; Glycation End Products, Advanced - metabolism; Humans; Inflammation; Macrophage Colony-Stimulating Factor - biosynthesis; Macrophage Colony-Stimulating Factor - cerebrospinal fluid; Medical research; Mice; Microglia; Neuroblastoma; Neurons; Neurons - drug effects; Neurons - physiology; NF-kappa B - metabolism; Oxidative Stress; Peptides; Receptor for Advanced Glycation End Products; Receptors, Immunologic - physiology; Recombinant Fusion Proteins - biosynthesis; Reference Values; Transfection; Tumor Cells, Cultured; Vascular Cell Adhesion Molecule-1 - biosynthesis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.10.5296

In Alzheimer disease (AD), neurons are thought to be subjected to the deleterious cytotoxic effects of activated microglia. We demonstrate that binding of amyloidbeta peptide (Aβ ) to neuronal Receptor for Advanced Glycation Endproduct (RAGE), a cell surface receptor for Aβ , induces macrophage-colony stimulating factor (M-CSF) by an oxidant sensitive, nuclear factor κ B-dependent pathway. AD brain shows increased neuronal expression of M-CSF in proximity to Aβ deposits, and in cerebrospinal fluid from AD patients there was ≈ 5-fold increased M-CSF antigen (P < 0.01), compared with age-matched controls. M-CSF released by Aβ -stimulated neurons interacts with its cognate receptor, c-fms, on microglia, thereby triggering chemotaxis, cell proliferation, increased expression of the macrophage scavenger receptor and apolipoprotein E, and enhanced survival of microglia exposed to Aβ , consistent with pathologic findings in AD. These data delineate an inflammatory pathway triggered by engagement of Aβ on neuronal RAGE. We suggest that M-CSF, thus generated, contributes to the pathogenesis of AD, and that M-CSF in cerebrospinal fluid might provide a means for monitoring neuronal perturbation at an early stage in AD.