Latest progress in the research of protein kinase C(PKC)isoform-specific signaling and PKC-modulated autophagy in ischemic stroke

Ischemic stroke is a major cause of morbidity and mortality,and currently there is no effective treatment.The family of protein kinase C(PKCs)could phosphorylate serine or threonine residues of its substrate proteins and play a key role in the ischemia/reperfusion injury.Autophagy is essential for maintaining cell homeostasis under physiological condition and acts as a double-edged sword in the process of ischemic neuronal death.In this article,we reviewed the PKCs isoform-specific signaling pathways and PKC-modulated autophagy in ischemic stroke.

BICAO-induced ischaemia caused depressive-like behaviours and caspase-8/-9-dependent brain regional neural cell apoptosis in mice

Introduction Cerebral ischaemia-induced depression is among the most frequent neuropsychiatric consequences and adversely impact the prognosis and recovery of patients.Although several brain regions have been implied in the development of ischaemia-induced depression,the brain region-specific neural cell apoptosis pathways have not been clarified yet.Methods In this study,bilateral internal carotid artery occlusion(BICAO)mouse model was established to induce cerebral ischaemia.Sucrose preference,tail suspension and forced swim tests were conducted on mice at 7,21 and 30 days after BICAO treatment.In addition,brain regional ischaemic neuron loss was investigated by using immunofluorescent staining of neuronal nuclei(NeuN)and caspase-8/-9-dependent cell apoptosis was also examined by western blot analysis.results BICAO-induced cerebral ischaemia resulted in decreased sucrose preference and increased immobility times,which were representative depressive-like behaviours of mice until 30 days after BICAO treatment compared with Sham-operated mice.This outcome was associated with significant neuron loss by using immunofluorescent staining and increased cleavage levels of pro-caspase-3/-8/-9,but not pro-caspase-12,by western blot analysis in hypothalamus,midbrain,prefrontal cortex and hippocampus of mice.Conclusions This study showed that BICAO-induced ischaemia caused depressive-like behaviours and caspase-8/-9-dependent neural cell apoptosis in several brain regions,including hypothalamus and midbrain of mice.

cPKCγ Deficiency Exacerbates Autophagy Impairment and Hyperphosphorylated Tau Buildup through the AMPK/mTOR Pathway in Mice with Type 1 Diabetes Mellitus

Type 1 diabetes mellitus(T1DM)-induced cognitive dysfunction is common,but its underlying mechanisms are still poorly understood.In this study,we found that knockout of conventional protein kinase C(cPKC)γsignificantly increased the phosphorylation of Tau at Ser214 and neurofibrillary tangles,but did not affect the activities of GSK-3βand PP2A in the hippocampal neurons of T1DM mice.cPKCγdeficiency significantly decreased the level of autophagy in the hippocampal neurons of T1DM mice.Activation of autophagy greatly alleviated the cognitive impairment induced by cPKCγdeficiency in T1DM mice.Moreover,cPKCγdeficiency reduced the AMPK phosphorylation levels and increased the phosphorylation levels of mTOR in vivo and in vitro.The high glucose-induced Tau phosphorylation at Ser214 was further increased by the autophagy inhibitor and was significantly decreased by an mTOR inhibitor.In conclusion,these results indicated that cPKCγpromotes autophagy through the AMPK/mTOR signaling pathway,thus reducing the level of phosphorylated Tau at Ser214 and neurofibrillary tangles.