Presenilin mediates neuroprotective functions of ephrinB and brain-derived neurotrophic factor and regulates ligand-induced internalization and metabolism of EphB2 and TrkB receptors
| Autor: | Zhiping Shao, Nikolaos K. Robakis, Julien Bruban, Jindong Xu, Junichi Shioi, Julie Dunys, Anastasios Georgakopoulos, Gweltas Mauger, Yimin Ren, Gael Barthet, Zhao Xuan, Nicolas Arbez |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Aging
Cell Survival Receptor EphB2 Excitotoxicity Ephrin-B2 Tropomyosin receptor kinase B medicine.disease_cause Neuroprotection Article Mice Neurotrophic factors mental disorders medicine Presenilin-1 Animals Receptor trkB Brain-derived neurotrophic factor Cerebral Cortex Mice Knockout Neurons Chemistry General Neuroscience Brain-Derived Neurotrophic Factor Glutamate receptor Erythropoietin-producing hepatocellular (Eph) receptor Rats nervous system Neurology (clinical) Geriatrics and Gerontology Signal transduction Neuroscience Developmental Biology Signal Transduction |
| Zdroj: | Neurobiology of aging. 34(2) |
| ISSN: | 1558-1497 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect