PMID- 22475621 OWN - NLM STAT- MEDLINE DCOM- 20130429 LR - 20211021 IS - 1558-1497 (Electronic) IS - 0197-4580 (Print) IS - 0197-4580 (Linking) VI - 34 IP - 2 DP - 2013 Feb TI - Presenilin mediates neuroprotective functions of ephrinB and brain-derived neurotrophic factor and regulates ligand-induced internalization and metabolism of EphB2 and TrkB receptors. PG - 499-510 LID - S0197-4580(12)00173-X [pii] LID - 10.1016/j.neurobiolaging.2012.02.024 [doi] AB - 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 gamma-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. CI - Copyright (c) 2013 Elsevier Inc. All rights reserved. FAU - Barthet, Gael AU - Barthet G AD - Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA. FAU - Dunys, Julie AU - Dunys J FAU - Shao, Zhiping AU - Shao Z FAU - Xuan, Zhao AU - Xuan Z FAU - Ren, Yimin AU - Ren Y FAU - Xu, Jindong AU - Xu J FAU - Arbez, Nicolas AU - Arbez N FAU - Mauger, Gweltas AU - Mauger G FAU - Bruban, Julien AU - Bruban J FAU - Georgakopoulos, Anastasios AU - Georgakopoulos A FAU - Shioi, Junichi AU - Shioi J FAU - Robakis, Nikolaos K AU - Robakis NK LA - eng GR - R01 NS047229/NS/NINDS NIH HHS/United States GR - AG-08200/AG/NIA NIH HHS/United States GR - AG-17926/AG/NIA NIH HHS/United States GR - R01 AG008200/AG/NIA NIH HHS/United States GR - NS 047229/NS/NINDS NIH HHS/United States GR - R01 NS047229-08/NS/NINDS NIH HHS/United States GR - R37 AG017926-13/AG/NIA NIH HHS/United States GR - R01 AG017926/AG/NIA NIH HHS/United States GR - R37 AG017926/AG/NIA NIH HHS/United States GR - R01 AG008200-23/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20120403 PL - United States TA - Neurobiol Aging JT - Neurobiology of aging JID - 8100437 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Ephrin-B2) RN - 0 (Presenilin-1) RN - EC 2.7.10.1 (Receptor, EphB2) RN - EC 2.7.10.1 (Receptor, trkB) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/*pharmacology MH - Cell Survival/drug effects/physiology MH - Cerebral Cortex/cytology/drug effects/*metabolism MH - Ephrin-B2/*pharmacology MH - Mice MH - Mice, Knockout MH - Neurons/cytology/drug effects/*metabolism MH - Presenilin-1/genetics/*metabolism MH - Rats MH - Receptor, EphB2/genetics/*metabolism MH - Receptor, trkB/genetics/*metabolism MH - Signal Transduction/drug effects/physiology PMC - PMC3394882 MID - NIHMS360868 EDAT- 2012/04/06 06:00 MHDA- 2013/04/30 06:00 PMCR- 2014/02/01 CRDT- 2012/04/06 06:00 PHST- 2012/01/25 00:00 [received] PHST- 2012/02/21 00:00 [revised] PHST- 2012/02/24 00:00 [accepted] PHST- 2012/04/06 06:00 [entrez] PHST- 2012/04/06 06:00 [pubmed] PHST- 2013/04/30 06:00 [medline] PHST- 2014/02/01 00:00 [pmc-release] AID - S0197-4580(12)00173-X [pii] AID - 10.1016/j.neurobiolaging.2012.02.024 [doi] PST - ppublish SO - Neurobiol Aging. 2013 Feb;34(2):499-510. doi: 10.1016/j.neurobiolaging.2012.02.024. Epub 2012 Apr 3.