Explore the Role of Abeta in Axonal Trafficking Deficits Induced by Alpha Synuclein in Parkinson Disease Mouse Model

Alpha synuclein (ASYN) is a neuronal protein that is observed in significant amounts in the brain and is encoded for by the SNCA gene, it functions as a regulator for the trafficking of synaptic vesicles. It has been noted that the buildup of alpha synuclein has been found in the form of Lewy bodies in studies involving patients with Parkinson’s diseases (PD). Gathering an understanding for the manner in which alpha synuclein affects the synaptic structure and the movement of axonal trafficking will help further our understanding towards the formation of Lewy bodies. Experimenting with the way in which ASYN affected the intervention of Abeta was important, to see the toxicity of Abeta in axonal trafficking. The PD and SynKO mouse models treated with Abeta both showed an effect on the anterograde moving speed of both the PD and SynKO neurons. Synaptic formation was examined, and it was found that ASYN had a large negative influence on the synapse formation in PD neurons. This was due to the significantly reduced colocalization that was found in the treated neurons. It was confirmed that ASYN caused neuronal atrophy through the over expression of GFP-ASYNWT wild type or the GFP-ASYNA53T. Comprehending ASYN effect on the axonal trafficking and the synaptic structure of PD neurons can help understand the mechanism that may be present which possibly stimulates Alzheimer’s Disease in PD patients.

Comparison of Brain-derived Neurotrophic Factor Level in Depressed Patients Treated with Fluoxetine and Sertraline

Background: The Brain-Derived NeurotrophicFactor (BDNF) is the main neuronal growth factor in the brain that regulates neurogenesis, neuronal maturity, synaptic formation and plasticity. Studies showed BDNF level decreased in depression and the administration of anti depressant drugs increased BDNF level. In this study, we used fluoxetine and sertraline, which are Selective Serotonin Reuptake Inhibitor (SSRI) but had a different mechanism in influencing the BDNF levels. The purpose of this study was to compare the effect of fluoxetine and sertraline administration tothe BDNF level in depressed subjects. This study was conducted at Wahidin Sudirohusodo Hospital, Makassar, Indonesia and its affiliates from January to February 2019. Twenty outpatient subjects were diagnosed with depression based on DSM-V. The subjects were either antidepressant naïve, or dropping out of antidepressant therapy for at least 3 months since the last administration. Blood samples from each subject were taken by consecutive sampling, and BDNF levels were analyzed before and after administration of fluoxetine and sertraline for six weeks. Also, Hamilton Depression Rating Scale (HDRS) scores are measured before and after administration. The BDNF serum was significantly increased by 100.6% (p<0,001) from the baseline level in the fluoxetine group and 75.4% in the sertraline group. HDRS score was decreased by39.5% (p<0,001) in the fluoxetine group and 30.1% in the sertraline group after six weeks of administration. This study suggests that fluoxetine was superior to sertraline in increasing the BDNF level in depression.

Running Promotes Transformation of Brain Astrocytes Into Neuroprotective Reactive Astrocytes and Synaptic Formation by Targeting Gpc6 Through the STAT3 Pathway

Ischemic stroke is caused by cerebral ischemia upon the blockage of an artery, which results in a high disability rate. Little is known regarding the mechanism of astrocyte function in cerebral ischemia. We aimed to determine the effects of running on the transformation of astrocytes, and subsequent synapse formation. A study of middle cerebral artery occlusion (MCAO) after running in vivo showed that running can promote the transformation of astrocytes toward the neuroprotective phenotype. Our findings of oxygen-glucose deprived astrocytes in vitro after running revealed that these astrocytes transformed into the neuroprotective phenotype, and that the expression of STAT3 and Gpc6 was increased. We confirmed that mechanistically, running can target Gpc6 through the STAT3 pathway and then regulate the number of synapses. We concluded that running promotes synapse proliferation by polarizing astrocytes toward the neuroprotective phenotype and ultimately leads to nerve regeneration.

Thrombopoietin Receptor Agonist Eltrombopag Prevents Insulin Resistance and Synaptic Pathology via HIF1α/COX2/Sirt1 Signaling Pathway

Background: Insulin resistance has been reported to be closely correlated with the pathogenesis of MHE. The mechanism underlying the effects of thrombopoietin receptor agonist eltrombopag (ELT) on synaptic activity and formation involved in MHE pathogenesis remains unclear. Methods: The effect of ELT on neurodegeneration and insulin resistance was examined in the primary rat neurons and an MHE rat model. Results: We found that the level of thrombopoietin receptor c-MPL (MPL) expression was decreased in MHE brains, and ELT administration improved insulin resistance, alleviated the destruction of synaptic formation and enhanced learning and memory in the MHE rats, indicating the relationship between dowregulated ELT and insulin resistance. Then in vitro, ELT treatment ameliorated the impairment of glucose uptake, indicating the reduction of insulin resistance. High dose of glucose inhibited insulin-stimulated downregulation of Hypoxia-inducible factor-1α (HIF1α) expression, the inhibition of inflammatory response and upregulation of sirtuin-1 (Sirt1), destruction of synaptic formation and activity, which were all reversed by ELT treatment in insulin resistant neurons.Conclusions: These results indicate that ELT is a promising potential therapeutic agent for insulin resistance and defect in learning and memory.

Thrombopoietin receptor agonist eltrombopag prevents insulin resistance-mediated synaptic pathology via HIF1α/GSK3β/Sirt1 pathway

Background Minimal hepatic encephalopathy (MHE) is characterized by impaired cognitive function and memory loss, which are often the result of synaptic pathology. Insulin resistance has been reported to be closely correlated with the pathogenesis of MHE. Methods The effect of thrombopoietin receptor agonist eltrombopag (ELT) on neurodegeneration and insulin resistance was examined in the primary rat neurons and an MHE rat model. Results We found that the level of thrombopoietin receptor c-MPL (MPL) expression was decreased in MHE brains, and ELT administration improved insulin resistance, alleviated the destruction of synaptic formation and enhanced learning and memory in the MHE rats, indicating the relationship between dowregulated ELT and insulin resistance. Then in vitro, ELT treatment ameliorated the impairment of glucose uptake, indicating the reduction of insulin resistance. High dose of glucose inhibited insulin-stimulated downregulation of Hypoxia-inducible factor-1α (HIF1α) expression, the phosphorylation of GSK3β (pGSK3 β), upregulation of sirtuin-1 (Sirt1), destruction of synaptic formation and activity, which were all reversed by ELT treatment in insulin resistant neurons. Conclusions These results indicate that ELT is a promising potential therapeutic agent for insulin resistance and defect in learning and memory.

Binary scaffold facilitates in situ regeneration of axons and neurons for complete spinal cord injury repair

A binary-drug modified scaffold is able to promote both axonal and neuronal regeneration in complete spinal cord injury model. Moreover, it also facilitates synaptic formation of the regenerated neurons and axons for motor function improvement.

The HSPG Syndecan is a core organizer of cholinergic synapses in C. elegans

SUMMARYThe extracellular matrix has emerged as an active component of chemical synapses regulating synaptic formation, maintenance and homeostasis. The heparan sulfate proteoglycan syndecans are known to regulate cellular and axonal migration in the brain. They are also enriched at synapses, but their synaptic functions remain more elusive. Here we show that SDN-1, the sole ortholog of syndecan in C. elegans, is absolutely required for the synaptic clustering of homomeric α7-like N-acetylcholine receptors (AChR) and regulates the synaptic content of heteromeric L-AChRs. SDN-1 is concentrated at neuromuscular junctions (NMJs) by the neurally-secreted synaptic organizer Ce-Punctin/MADD-4, which also activates the transmembrane netrin receptor DCC. Those cooperatively recruit the FARP and CASK orthologues that localize N-AChRs at cholinergic NMJs through physical interactions. Therefore, SDN-1 stands at the core of the cholinergic synapse organization by bridging the extracellular synaptic determinants to the intracellular synaptic scaffold that controls the postsynaptic receptor content.