Elevated Plasma Levels of Drebrin in Glaucoma Patients With Neurodegeneration

Glaucoma is an optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs). Aberrations in several cytoskeletal proteins, such as tau have been implicated in the pathogenesis of neurodegenerative diseases, could be initiating factors in glaucoma progression and occurring prior to axon degeneration. Developmentally regulated brain protein (Drebrin or DBN1) is an evolutionarily conserved actin-binding protein playing a prominent role in neurons and is implicated in neurodegenerative diseases. However, the relationship between circulating DBN1 levels and RGC degeneration in glaucoma patients remains unclear. In our preliminary study, we detected drebrin protein in the plasma of glaucoma patients using proteomic analysis. Subsequently, we recruited a total of 232 patients including primary angle-closure glaucoma (PACG), primary open-angle glaucoma (POAG) and Posner-Schlossman syndrome (PS) and measured its DBN1 plasma levels. We observed elevated DBN1 plasma levels in patients with primary glaucoma but not in patients with PS compared to nonaxonopathic controls. Interestingly, in contrast to tau plasma levels increased in all groups of patients, elevated drebrin plasma levels correlated with retinal nerve fiber layer defect (RNFLD) in glaucoma patients. To further explore the expression of DBN1 in neurodegeneration, we conducted experiment of optic nerve crush (ONC) models, and observed increased expression of DBN1 in the serum as well as in the retina and then decreased after ONC. This result reinforces the potentiality of circulating DBN1 levels are increased in glaucoma patients with neurodegeneration. Taken together, our findings suggest that circulating DBN1 levels correlated with RNFLD and may reflect the severity of RGCs injury in glaucoma patients. Combining measurement of circulating drebrin and tau levels may be a useful indicator for monitoring progression of neurodegenerative diseases

Levitin-Polyak well-posedness for generalized semi-infinite multiobjective programming problems

Abstract In this paper, we introduce a notion of Levitin-Polyak well-posedness for generalized semi-infinite multiobjective programming problems in terms of weakly efficient solutions. We obtain some metric characterizations of Levitin-Polyak well-posedness for this problem. We derive the relations between the Levitin-Polyak well-posedness and the upper semi-continuity of approximate solution maps for generalized semi-infinite multiobjective programming problems. Examples are given to illustrate our main results

Inhibiting PTEN protects hippocampal neurons against stretch injury by decreasing membrane translocation of AMPA receptor GluR2 subunit.

The AMPA type of glutamate receptors (AMPARs)-mediated excitotoxicity is involved in the secondary neuronal death following traumatic brain injury (TBI). But the underlying cellular and molecular mechanisms remain unclear. In this study, the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in GluR2-lacking AMPARs mediated neuronal death was investigated through an in vitro stretch injury model of neurons. It was indicated that both the mRNA and protein levels of PTEN were increased in cultured hippocampal neurons after stretch injury, which was associated with the decreasing expression of GluR2 subunits on the surface of neuronal membrane. Inhibition of PTEN activity by its inhibitor can promote the survival of neurons through preventing reduction of GluR2 on membrane. Moreover, the effect of inhibiting GluR2-lacking AMPARs was similar to PTEN suppression-mediated neuroprotective effect in stretch injury-induced neuronal death. Further evidence identified that the total GluR2 protein of neurons was not changed in all groups. So inhibition of PTEN or blockage of GluR2-lacking AMPARs may attenuate the death of hippocampal neurons post injury through decreasing the translocation of GluR2 subunit on the membrane effectively

Inhibition of PTEN protects neurons from stretch-induced neuronal death.

<p><b>A</b>. Time course of stretch-induced hippocampal neuronal death.Representative images of PI uptake and staining for the neuronal marker NeuN showing stretch-induced delayed death in hippocampal neurons at 24 h. <b>B</b>. Summary data of PI uptake. Stretch- induced neuronal death was evident at 24 h after injury (*p<0.05, difference from sham, sham + Nas, sham + bpv groups; ^#p<0.05, difference from injury group, ^&p<0.05 difference from injury + Nas group, ^$p<0.05 difference from injury+bpv group. Scale bar = 75 µm.</p

Nas reduced PTEN over-expression induced neuronal death.

<p>A. Representative images showing there were more neuronal death in neurons transfected with PTEN-GFP and Nas attenuated PTEN over-expression induced neuronal death. Bar graph showing that neuronal death was significantly increased in neurons transfected with PTEN-GFP compared with those transfected with GFP and PTEN-GFP + Nas(bar = 50.17 µm, *p<0.05 compared with GFP, ^# p<0.05 compared with PTEN-GFP + Nas). B. Representative images showing there were PTEN expression in normal neurons transfected with PTEN-GFP and Nas has no effect on PTEN expression in cultured neurons. Bar graph showing that the expression of PTEN in neurons transfected with PTEN-GFP was significantly increased than those in GFP and GFP+Nas groups (*p<0.05 compared with control group and #p<0.05 compared with GFP+Nas groups).</p

Changes of surface GluR2 subunit expression in cultured hippocampal neurons post stretch injury.

<p>A. Representative images showing that surface expression of membrane GluR2 subunits was reduced after injury, but inhibition of PTEN activity by bpv increases the surface expression of GluR2 subunits. Bar graph showing expression of GluR2 subunits in the normal (control) , injury and injury + bpv treatment group (*p<0.05). Scale bar = 47.62 µm. B. Representative images of Western blot showing the total expression of whole GluR2 subunits in normal, injury and bpv groups. β-actin was used as a loading control. (n = 3 for each group; Compared with normal group: *p<0.05).</p

Expression of PTEN in cultured hippocampal neurons post stretch injury.

<p>A. Representative images of RT-PCR showing that the expression of PTEN mRNA increased post stretch injury in cultured rat hippocampal neurons (n = 3 for each group; Compared with normal group: **p<0.01, *p<0.05). B. Representative images of western blot showing that the expression of PTEN protein increased post stretch injury in cultured rat hippocampal neurons. (n = 3 for each group; Compared with normal group: **p<0.01, *p<0.05). β-actin was used as a loading control.</p