Microglia release activators of neuronal proliferation mediated by activation of mitogen-activated protein kinase, phosphatidylinositol-3-kinase/Akt and delta-Notch signalling cascades.
Microglia, the resident macrophage of the brain, can release substances that aid neuronal development, differentiation and survival. We have investigated the effects of non-activated microglia on the survival of cultured rat cerebellar granule neurones. Microglial-conditioned medium, collected from primary rat microglial cultures, was used to treat 7-day-in-vitro neurones, and neuronal viability and proliferation was assessed following a further 1 or 7 days in culture. Microglial-conditioned medium enhanced neuronal survival by up to 50% compared with untreated neurones and this effect was completely abated by pretreatment of the microglia with l-leucine methyl ester. The expression of the proliferation marker Ki-67 increased in neuronal cultures treated with microglial-conditioned medium suggesting enhanced proliferation of precursor neurones. Microglial-induced neuronal proliferation could be attenuated by specific inhibition of mitogen-activated protein kinase or phosphatidylinositol-3-kinase/Akt signalling pathways, and by selective fractionation and immunodepletion of the microglial-conditioned medium. Activation of the Notch pathway was enhanced as antibody against the Notch ligand, delta-1, prevented the microglial-induced neuronal proliferation. These results show that microglia release stable neurotrophic factors that can promote neuronal precursor cell proliferation.
Morgan
Sarah C
SC
Department of Neuroinflammation, Institute of Neurology, University College London, London, UK.
Taylor
Deanna L
DL
Pocock
Jennifer M
JM
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D051880:Receptors, Notch; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000906:Antibodies; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051880:Receptors, Notch; C064045:delta protein; C494920:Akt1 protein, rat