Presenilin mediates neuroprotective functions of ephrinB and brain-derived neurotrophic factor and regulates ligand-induced internalization and metabolism of EphB2 and TrkB receptors
Neurobiology of Aging. 2013-02-01; 34(2): 499-510
DOI: 10.1016/j.neurobiolaging.2012.02.024
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Barthet G(1), Dunys J, Shao Z, Xuan Z, Ren Y, Xu J, Arbez N, Mauger G, Bruban J,Georgakopoulos A, Shioi J, Robakis NK.
Author information:
(1)Center for Molecular Biology and Genetics of Neurodegeneration, Departments ofPsychiatry and Neuroscience, Mount Sinai School of Medicine, New York, NY 10029,USA.
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.
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