title: Presenilin mediates neuroprotective functions of ephrinB and brain-derived neurotrophic factor and regulates ligand-induced internalization and metabolism of EphB2 and TrkB receptors.
abstract: Activation of EphB receptors by ephrinB (efnB) ligands on neuronal cell surface regulates important functions, including neurite outgrowth, axonal guidance, and synaptic plasticity. Here, we show that efnB rescues primary cortical neuronal cultures from necrotic cell death induced by glutamate excitotoxicity and that this function depends on EphB receptors. Importantly, the neuroprotective function of the efnB/EphB system depends on presenilin 1 (PS1), a protein that plays crucial roles in Alzheimer's disease (AD) neurodegeneration. Furthermore, absence of one PS1 allele results in significantly decreased neuroprotection, indicating that both PS1 alleles are necessary for full expression of the neuroprotective activity of the efnB/EphB system. We also show that the ability of brain-derived neurotrophic factor (BDNF) to protect neuronal cultures from glutamate-induced cell death depends on PS1. Neuroprotective functions of both efnB and BDNF, however, were independent of γ-secretase activity. Absence of PS1 decreases cell surface expression of neuronal TrkB and EphB2 without affecting total cellular levels of the receptors. Furthermore, PS1-knockout neurons show defective ligand-dependent internalization and decreased ligand-induced degradation of TrkB and Eph receptors. Our data show that PS1 mediates the neuroprotective activities of efnB and BDNF against excitotoxicity and regulates surface expression and ligand-induced metabolism of their cognate receptors. Together, our observations indicate that PS1 promotes neuronal survival by regulating neuroprotective functions of ligand-receptor systems.
authors.affiliation: Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Gael
authors.initials: G
authors.lastname: Barthet
authors.forename: Julie
authors.initials: J
authors.lastname: Dunys
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Shao
authors.forename: Zhao
authors.initials: Z
authors.lastname: Xuan
authors.forename: Yimin
authors.initials: Y
authors.lastname: Ren
authors.forename: Jindong
authors.initials: J
authors.lastname: Xu
authors.forename: Nicolas
authors.initials: N
authors.lastname: Arbez
authors.forename: Gweltas
authors.initials: G
authors.lastname: Mauger
authors.forename: Julien
authors.initials: J
authors.lastname: Bruban
authors.forename: Anastasios
authors.initials: A
authors.lastname: Georgakopoulos
authors.forename: Junichi
authors.initials: J
authors.lastname: Shioi
authors.forename: Nikolaos K
authors.initials: NK
authors.lastname: Robakis
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D036388:Ephrin-B2 / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D036183:Receptor, EphB2 / Q000235:genetics / Q000378:metabolism*; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D036388:Ephrin-B2; D053764:Presenilin-1; D036183:Receptor, EphB2; D020813:Receptor, trkB