The granulocyte macrophage colony stimulating factor (GM-CSF) regulates amyloid beta (Abeta) production.
One of the hallmarks of Alzheimer's disease (AD) is the accumulation of amyloid beta (Abeta) plaques in the brain parenchyma. An inflammatory component to AD has been suggested in association with increased cytokine release. We have previously shown that CD40L stimulation of microglia induces increases in pro-inflammatory cytokines such as interleukin-1beta (IL-1beta), IL-6, IL-8 and GM-CSF. We have also shown that CD40L stimulation increases Abeta levels in HEK-293 cells over-expressing both the amyloid precursor protein (APP) and CD40 (HEK/APPsw/CD40). In this study, we show that GM-CSF neutralizing antibodies mitigate the CD40L-induced production of Abeta in HEK/APPsw/CD40 cells. In addition, we demonstrate that treatment of these cells with recombinant GM-CSF significantly increases Abeta levels. Furthermore, we show that shRNA silencing of the GM-CSF receptor gene significantly reduces Abeta levels to below base line in non-stimulated HEK/APPsw/CD40 cells. Analysis of cell surface proteins revealed that silencing of the GM-CSF receptor also decreases APP endocytosis (therefore reducing the availability of APP to be cleaved in the endosomes). Taken together, our results suggest that GM-CSF operates downstream of CD40/CD40L interaction and that GM-CSF modulates Abeta production by influencing APP trafficking. GM-CSF signaling may be a suitable therapeutic target against Abeta production in AD.
Volmar
Claude-Henry
CH
Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA.
Ait-Ghezala
Ghania
G
Frieling
Jeremy
J
Paris
Daniel
D
Mullan
Michael J
MJ
D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis; D000818:Animals; D023201:CD40 Ligand / Q000378:metabolism; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004705:Endocytosis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D034622:RNA Interference; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015398:Signal Transduction
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D023201:CD40 Ligand; D016178:Granulocyte-Macrophage Colony-Stimulating Factor