A Preliminary Study GFAP-mediated Autophagy In Depression Disease

Depression, one of the most common psychiatric diseases, affects theliving and survival status of approximate16%people in the world, and theworldwide incidence of depression gradually increased in recent years.However, the etiology and pathogenesis of depression is still unclear so far.The results of depression patients and animals suggest that different degreesof physiological dysfunction in astrocytes (Ast) directly influences theoneset of depression, but the molecular mechanism of Ast in the occurrenceand development of depression is not clear.Glial fibrillary acidic protein (GFAP) is a broad biomarker of Ast cell.Numerous studies show that GFAP is thought help to maintain a variety ofbiological functions in Ast, such as maintenance of the blood brain barrier,synaptic plasticity, cell proliferation, and regulation the vesicles andlysosomes in Ast transport and so on In the cerebral cortex and hippocampusof the limbic system and other key brain regions of depression patients,reduced protein level of GFAP may lead to Ast and neuronal apoptosis, aswell as the key reason for the change in certain brain loop. And GFAP canpass the blood-brain barrier, from brain into the blood circulation, so the changing protein levels of GFAP in the central nervous system andperipheral blood can react to Ast injury of neural degeneration. At present,GFAP has become a widely concerned new target of depression diseaseoccurrence, development and treatment.We examined the protein level of GFAP in the plasma of depressionpatients and rats by biologic molecular techniques. Depression SD ratswere experimented subjects to study the pathology and molecularmechanisms of chronic stress induced depression. And astroglioma U251cells were used as an in vitro cell model to explore the regulation effect ofknockdown GFAP on autophagy pathway. In this thesis, Western Blot, IHCand PCR methods were applied to investigate the molecular mechanism ofGFAP, a biomarker of Ast cells, in the occurrence and development indepression disease at the molecular level, cellular level and pathologicallevels.In this study, elevated GFAP protein level in the plasma of depressionpatients without treatment was been found at the first time. To itcorresponding is, GFAP protein level was also increased in the plasma ofdepression rats. Meanwhile, in the prefrontal cortex of depression rats, theexpression level of GFAP was significantly decreased. And the expressionlevels of autophagic proteins LC3-Ⅱ and Atg7were greatly increased,Atg3expression level was reduced in CUMS rats compared to normal rats.Moreover, STAT3and NF-B signaling cascades were activated, meanwhile, the AKT and mTOR pathways were suppressed in depression rats. Besides,Dopamine signaling pathway key regulatory proteins DJ-1, PINK1, SYN-1were also activated in the prefrontal cortex of depression rats.In addition, we used siRNA technology specific inhibited theexpression of GFAP in U251cells. And knockdown GFAP could inhibit theactivation of AKT, ERK and mTOR signal pathways in U251cells. Moreover,knockdown GFAP could also significantly upregulate the expression levels ofautophagic proteins LC3-Ⅱ, Atg3, Atg7, Atg12, and had no effects on theprotein levels of apoptotic protein Bax, Bcl-2and Caspase3in U251cells.In addition, inhibition of GFAP expression would regulate the dopaminesignaling pathway in U251cells. Therefore, as a key regulatory factor,GFAP play a crucial role in the pathogenesis of depression.