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Aims: SUMOylation is a posttranslational modification related to multiple human diseases. SUMOylation can be reversed by classes of proteases known as the sentrin/SUMO‐specific proteases (SENPs). In the present study, we investigate the potential role of SENP1 in pericytes in the brain ischemia. Methods: Pericyte‐specific deletion of senp1 mice (Cspg4‐Cre; senp1f/f) were used for brain function and neuronal damage evaluation following brain ischemia. The cerebral blood vessels of diameter, velocity, and flux were performed in living mice by two‐photon laser scanning microscopy (TPLSM). Biochemical analysis and immunohistochemistry methods were used to address the role and mechanism of pericyte‐specific SENP1 in the pathological process of brain ischemia. A coculture model of HBVPs and HBMECs mimicked the BBB in vitro and was used to evaluate BBB integrity after glucose deprivation. Results: Our results showed that senp1‐specific deletion in pericytes did not affect the motor function and cognitive function of mice. However, the pericyte‐specific deletion of senp1 aggravated the infarct size and motor deficit following focal brain ischemia. Consistently, the TPLSM data demonstrated that SENP1 deletion in pericytes accelerated thrombosis formation in brain microvessels. We also found that pericyte‐specific deletion of senp1 exaggerated the neuronal damage significantly following brain ischemia in mice. Moreover, SENP1 knockdown in pericytes could activate the apoptosis signaling and disrupt the barrier integrity in vitro coculture model. Conclusions: Our findings revealed that targeting SENP1 in pericytes may represent a novel therapeutic strategy for neurovascular protection in stroke. [ABSTRACT FROM AUTHOR]

Summary: Aims: Autism spectrum disorder (ASD) is a wide range of neurodevelopmental disorders involving deficits in social interaction and communication. Unfortunately, autism remains a scientific and clinical challenge owing to the lack of understanding the cellular and molecular mechanisms underlying it. This study aimed to investigate the pathophysiological mechanism underlying leukocyte‐endothelial adhesion in autism‐related neurovascular inflammation. Methods: Male BTBR T+tf/J mice were used as an autism model. The dynamic pattern of leukocyte‐endothelial adhesion in mouse cerebral vessels was detected by two‐photon laser scanning microscopy (TPLSM). Using FACS, RT‐PCR, and Western blotting, we explored the expression of cell adhesion molecules, the mRNA expression of endothelial chemokine, the protein levels of cathepsin B, and inflammatory mediators. Results: We found a significant increase in leukocyte‐endothelial adhesion in BTBR mice, accompanied by elevated expression of the adhesion molecule neutrophils CD11b and endothelial ICAM‐1. Our data further indicate that elevated neutrophil cathepsin B levels contribute to elevated endothelial chemokine CXCL7 levels in BTBR mice. The pharmacological inhibition of cathepsin B reverses the enhanced leukocyte‐endothelial adhesion in the cerebral vessels of autistic mice. Conclusion: Our results revealed the prominent role of cathepsin B in modulating leukocyte‐endothelial adhesion during autism‐related neurovascular inflammation and identified a promising novel approach for autism treatment. [ABSTRACT FROM AUTHOR]

Aims The receptor tyrosine kinase ErbB4 is present throughout the primate brain and has a distinct functional profile. In this study, we investigate the potential role of endothelial ErbB4 receptor signaling in the brain. Results Here, we show that the endothelial cell-specific deletion of ErbB4 induces decreased exploratory behavior in adult mice. However, the water maze task for spatial memory and the memory reconsolidation test reveal no changes; additionally, we observe no impairment in Ca MKII phosphorylation in Cdh5Cre;ErbB4 f/f mice, which indicates that the endothelial ErbB4 deficit leads to decreased exploratory activity rather than direct memory deficits. Furthermore, decreased brain metabolism, which was measured using micro-positron emission tomography, is observed in the Cdh5Cre;ErbB4 f/f mice. Consistently, the immunoblot data demonstrate the downregulation of brain Glut1, phospho- ULK1 (Ser555), and TIGAR in the endothelial ErbB4 conditional knockout mice. Collectively, our findings suggest that endothelial ErbB4 plays a critical role in regulating brain function, at least in part, through maintaining normal brain energy homeostasis. Conclusions Targeting ErbB4 or the modulation of endothelial ErbB4 signaling may represent a rational pharmacological approach to treat neurological disorders. [ABSTRACT FROM AUTHOR]

Background Autism spectrum disorders ( ASDs) are a heterogeneous group of neurodevelopmental disorders that display complicated behavioral symptoms. Methods Using gene expressing profiling and the weighted gene co-expression network analysis ( WGCNA), we studied genes coregulated by similar factors such as genetic variants or environmental effects in the hippocampus in an animal model of autism. Results From microarray data, we identified 21,388 robustly expressed genes of which 721 genes were found to be differently expressed in the valproic acid-treated group compared to the control group. WGCNA identified multiple co-expression modules known to associate with cognitive function, inflammation, synaptic, and positive regulation of protein kinase activating. Many of these modules, however, have not been previously linked to autism spectrum disorders which included G-protein signaling, immunity, and neuroactive ligand-receptor interaction pathway. The downregulation of the highly connected (hub) genes Taar7h and Taar7b in neuroactive ligand-receptor interaction pathway was validated by qRT- PCR. Immunoblotting and immunohistochemistry further showed that TAAR7 expression was downregulated not only in valproic acid-treated animals, but also BTBR T+tf/J mice. Conclusions This study highlights the advantages of gene microarrays to uncover co-expression modules associated with autism and suggests that Taars and related gene regulation networks may play a significant role in autism. [ABSTRACT FROM AUTHOR]

Aim It is now clear that insulin signaling has important roles in regulation of neuronal functions in the brain. Dysregulation of brain insulin signaling has been linked to neurodegenerative disease, particularly Alzheimer's disease ( AD). In this regard, there is evidence that improvement of neuronal insulin signaling has neuroprotective activity against amyloid β (A β)-induced neurotoxicity for patients with AD. Linagliptin is an inhibitor of dipeptidylpeptidase-4 ( DPP-4), which improves impaired insulin secretion and insulin downstream signaling in the in peripheral tissues. However, whether the protective effects of linagliptin involved in A β-mediated neurotoxicity have not yet been investigated. Methods In the present study, we evaluated the mechanisms by which linagliptin protects against A β-induced impaired insulin signaling and cytotoxicity in cultured SK-N- MC human neuronal cells. Results Our results showed that A β impairs insulin signaling and causes cell death. However, linagliptin significantly protected against A β-induced cytotoxicity, and prevented the activation of glycogen synthase kinase 3 β ( GSK3 β) and tau hyperphosphorylation by restoring insulin downstream signaling. Furthermore, linagliptin alleviated A β-induced mitochondrial dysfunction and intracellular ROS generation, which may be due to the activation of 5′ AMP-activated protein kinase ( AMPK)-Sirt1 signaling. This upregulation of Sirt1 expression was also observed in diabetic patients with AD coadministration of linagliptin. Conclusions Taken together, our findings suggest linagliptin can restore the impaired insulin signaling caused by A β in neuronal cells, suggesting DPP-4 inhibitors may have therapeutic potential for reducing A β-induced impairment of insulin signaling and neurotoxicity in AD pathogenesis. [ABSTRACT FROM AUTHOR]

Aims Diabetes mellitus increases the risk of stroke, but the mechanisms are unclear. The present study tested the hypothesis that diabetes mellitus disturbs the brain microcirculation and increases the susceptibility to cerebral damage in a middle cerebral artery occlusion ( MCAO) model of ischemia. Methods Diabetes was induced by streptozocin in mice expressing green fluorescent protein in endothelial cells (Tie2- GFP mice). Four weeks later, they were subjected to transient (20 min) MCAO. In vivo blood flow was measured by two-photon laser-scanning microscopy ( TPLSM) in cerebral arteries, veins, and capillaries. Results There was a significant decrease in red blood cell ( RBC) velocity in capillaries in diabetic mice as assessed by TPLSM, yet the regional cerebral blood flow, as assessed by laser Doppler flowmetry, was maintained. Brain capillary flow developed turbulence after MCAO only in diabetic mice. These mice sustained increased neurological deficits after MCAO which were accompanied by an exaggerated degradation of tight junction proteins and blunted Ca MKII phosphorylation in cerebral tissues indicating disruption of the blood-brain barrier and disturbed cognitive potential. Conclusion Diabetic mice are more susceptible to disturbances of cerebral capillary blood flow which may predispose them to neurovascular defects following ischemia. [ABSTRACT FROM AUTHOR]

Background Defining the impact of diabetes and related risk factors on brain cognitive function is critically important for patients with diabetes. Aims To investigate the alterations in hippocampal serine/threonine kinases signaling in the early phase of type 1 and type 2 diabetic rats. Methods Early experimental diabetes mellitus was induced in rats with streptozotocin or streptozotocin/high fat. Changes in the phosphorylation of proteins were determined by immunoblotting and immunohistochemistry. Results Our data showed a pronounced decrease in the phosphorylation of Ca2+/calmodulin-dependent protein kinase II (Ca MKII) in the hippocampi of both type 1 and type 2 diabetic rats compared with age-matched control rats. Unexpectedly, we found a significant increase in the phosphorylation of synapsin I ( Ser 603) and Glu R1 ( Ser 831) in the same experiment. In addition, aberrant changes in hippocampal protein kinase C ( PKC) and protein kinase A ( PKA) signaling in type 1 and type 2 diabetic rats were also found. Moreover, PP1α and PP2 A protein levels were decreased in the hippocampus of type 1 diabetic rats, but significantly up-regulated in type 2 diabetic rats. Conclusions The disturbance of Ca MKII/ PKA/ PKC phosphorylation in the hippocampus is an early change that may be associated with the development and progression of diabetes-related cognitive dysfunction. [ABSTRACT FROM AUTHOR]

Background Tight junction protein degradation is a principal characteristic of the blood-brain barrier ( BBB) damage that occurs during brain ischemia. Aims We investigated the mechanisms of occludin degradation that underlie permanent middle cerebral artery occlusion (p MCAO) in rats. Methods and Results Western blot and Co-immunoprecipitation data indicated ubiquitination and degradation of occludin in brain after p MCAO, which was consistent with ZO-1 degradation in penumbra regions as observed at 24 h after p MCAO. We further investigated candidate protease(s) responsible for the degradation of occludin during p MCAO. The intraventricular administration of γ-secretase blocker DAPT significantly inhibited the p MCAO-induced neurovascular damage, whereas ALLM and Batimastat, which are inhibitors of calpain and metalloproteinase proteases, respectively, were less effective. Notably, we found that DAPT significantly inhibited BBB disruption in comparison with vehicle treatment, as assessed by Evans blue excretion. Interestingly, the confocal immunostaining revealed that activation of the E3 ubiquitin ligase Itch is associated with degradation of occludin in brain microvessels following ischemia. Furthermore, our data demonstrate that the inhibition of γ-secretase signaling and the itch-mediated ubiquitination of occludin likely underlie the vasoprotective effect of DAPT after p MCAO. Conclusion The γ-secretase blocker DAPT reduces the permeability of the BBB by decreasing the ubiquitination and degradation of occludin during permanent brain ischemia, suggesting that γ-secretase may represent a novel therapeutic target for preventing neurovascular damage. [ABSTRACT FROM AUTHOR]