Locus coeruleus-CA1 projections are involved in chronic depressive stress-induced hippocampal vulnerability to transient global ischaemia.

Depression and transient ischaemic attack represent the common psychological and neurological diseases, respectively, and are tightly associated. However, studies of depression-affected ischaemic attack have been limited to epidemiological evidences, and the neural circuits underlying depression-modulated ischaemic injury remain unknown. Here, we find that chronic social defeat stress (CSDS) and chronic footshock stress (CFS) exacerbate CA1 neuron loss and spatial learning/memory impairment after a short transient global ischaemia (TGI) attack in mice. Whole-brain mapping of direct outputs of locus coeruleus (LC)-tyrosine hydroxylase (TH, Th:) positive neurons reveals that LC-CA1 projections are decreased in CSDS or CFS mice. Furthermore, using designer receptors exclusively activated by designer drugs (DREADDs)-based chemogenetic tools, we determine that Th:LC-CA1 circuit is necessary and sufficient for depression-induced aggravated outcomes of TGI. Collectively, we suggest that Th:LC-CA1 pathway plays a crucial role in depression-induced TGI vulnerability and offers a potential intervention for preventing depression-related transient ischaemic attack.

Cdk5 suppression blocks SIRT1 degradation via the ubiquitin-proteasome pathway in Parkinson's disease models.

The NAD+-dependent protein deacetylase sirtuin 1 (SIRT1), a member of the sirtuin family, may have a neuroprotective effect in multiple neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Many studies have suggested that overexpression-induced or resveratrol-treated activation of SIRT1 could significantly ameliorate several neurodegenerative diseases in mouse models. However, the type of SIRT1, protein expression levels and underlying mechanisms remain unclear, especially in PD. In this study, the results demonstrated that SIRT1 knockout markedly worsened the movement function in MPTP-lesioned animal model of PD. SIRT1 expression was found to be markedly decreased not only in environmental factor PD models, neurotoxin MPP+-treated primary culture neurons and MPTP-induced mice but also in genetic factor PD models, overexpressed α-synuclein-A30PA53T SH-SY5Y stable cell line and hm2α-SYN-39 transgenic mouse strain. Importantly, the degradation of SIRT1 during MPP+ treatment was mediated by the ubiquitin-proteasome pathway. Furthermore, the results indicated that cyclin-dependent kinase 5 (Cdk5) was also involved in the decrease of SIRT1 expression, which could be efficiently blocked by the inhibition of Cdk5. In conclusion, our findings revealed that the Cdk5-dependent ubiquitin-proteasome pathway mediated degradation of SIRT1 plays a vital role in the progression of PD.

CDK5-mediated phosphorylation of Sirt2 contributes to depressive-like behavior induced by social defeat stress.

Major depressive disorder (MDD) is a common, severe and recurrent psychiatric disorder worldwide; however, the underlying neuropathological mechanisms remain elusive. Histone deacetylases (HDACs) appear to play an essential role in depression. As the class III HDACs, Sirt1 and Sirt2 have attracted the most interest in the nervous system. Indeed, chronic stress decreased Sirt1 activity and down-regulated Sirt1 gene expression in MDD. Nevertheless, there is a paucity of literature on the role of Sirt2. To study the role of Sirt2 we established a MDD mouse model in wild type and Sirt2 knockout C57BL/6 mice using social defeat stress (SDS). We found that a lack of Sirt2 blocked the development of SDS-induced depressive-like behavior. Moreover, SDS led to Sirt2 phosphorylation in the amygdala without changing total Sirt2 levels, and blocking the phosphorylation of Sirt2 by CDK5 at serine residues 368 and 372 prevented SDS-induced depressive-like behavior and Sirt2 nuclear import. We also discovered that SDS-induced Sirt2 phosphorylation was involved in VTA-amygdala modulation using TetTag-pharmacogenetic method. These results suggest that CDK5 mediates phosphorylation of Sirt2 in the amygdala and contributes to the depressive-like behavior induced by SDS. This study highlights that inhibiting CDK5-dependent phosphorylation of Sirt2 at serine residues 368 and 372 by myristoylated membrane-permeabilising peptide (Sirt2-p), rather than using non-specific sirtuin inhibitors, may be a novel strategy for treating depression.

Cdk5-Dependent Activation of Neuronal Inflammasomes in Parkinson's Disease.

BACKGROUND: Inflammasomes, which mediate the activation of caspase-1 and maturation of IL-1ß and IL-18, have been unambiguously verified to participate in many diseases, such as lung diseases, infectious diseases and Alzheimer's disease, but the relation between Parkinson's disease and inflammasomes is poorly understood. METHODS: The expression, maturation, and secretion of inflammasomes in neurons were measured. The activation of inflammasomes in the substantia nigra of the brain was tested in acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and an α-synuclein transgenic mouse model. The levels of IL-1ß and IL-18 in cerebrospinal fluid and serum samples of Parkinson's disease (PD) patients and control subjects were measured. The role of cyclin-dependent kinase 5 (Cdk5) in neuronal inflammasome activation was evaluated using the pharmacological Cdk5 inhibitor roscovitine or Cdk5-targeted deletion. RESULTS: Here, we observed the expression of core molecules of inflammasomes, including NALP3, ASC, caspase-1, and IL-1ß, in neuronal cells. The PD inducer rotenone could activate neuronal inflammasomes and promote the maturation and secretion of the cleaved IL-1ß and IL-18 in a dose- and time-dependent manner. We also detected the activation of inflammasomes in the substantia nigra of a PD mouse model and in cerebrospinal fluid of PD patients. Furthermore, Cdk5 is required for the activation of inflammasomes, and both inhibition and deletion of Cdk5 could efficiently block inflammasome activation in PD models. CONCLUSIONS: Together, our results indicated that Cdk5-dependent activation of neuronal inflammasomes was involved in the progression of PD.

Phosphorylation of Connexin 43 by Cdk5 Modulates Neuronal Migration During Embryonic Brain Development.

The gap junction protein, connexin 43 (Cx43), is only present and abundantly expressed in astrocytes but is absent in neurons in the mature brain tissues. However, both the expression and function of Cx43 in neurons during brain embryonic development remain largely unexplored. In the present study, we confirmed that Cx43 is expressed in the migrating neurons in the embryonic stage of the brain. Neuron-specific Cx43 conditional knockout (cKO) using Cre-loxP technique impairs neuronal migration and formation of laminar structure in cerebral cortex during brain embryonic development. The animal behavior tests demonstrated that, at the adult stage, neuronal Cx43 cKO mice exhibit normal learning and memory functions but increased anxiety-like behavior. We also found that during the embryonic development, the gradually decreased Cx43 expression in the cortex is closely correlated with the upregulation of cyclin-dependent kinase 5 (Cdk5) activity. Cdk5 directly phosphorylates Cx43 at Ser279 and Ser282, which, in consequence, inhibits the membrane targeting of Cx43 and promotes its proteasome-dependent degradation. In summary, our findings revealed that the embryonic expression of Cx43 in neurons regulates processes of neuronal migration and positioning in the developing brain by controlling astrocyte-neuron interactions during brain embryonic development, and Cdk5 directly phosphorylates Cx43, which regulates the membrane localization and degradation of Cx43 in neurons.

[Effects of Dureping Injection on the contents of MMP-9 and TIMP-1 in the lung tissue of mice with pneumonia of influenza virus infection].

OBJECTIVE: To observe the effects of Dureping Injection on the contents of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in the lung tissue of mice with pneumonia of influenza virus infection. METHODS: Sixty-six ICR mice were randomly divided into the normal group, the model group, the low, middle, and high dose Dureping Injection groups (0.435, 0.870, and 1.740 mg/d, respectively), and the positive control group (Ribavirin, 2.500 mg/d), 11 in each. The pneumonia of mice with influenza virus infection model was established using influenza virus strain FM1. Mice were intraperitoneally injected with 0. 3 mL FM1 starting from the infection day, once daily. Five days later mice were killed to calculate the lung index. The pathomorphological changes of the lung tissue were observed using routine HE stained sections. The contents of MMP-9 and TIMP-1 in the homogenate of the lung tissue were detected by ELISA double antibody sandwich method. RESULTS: Compared with the normal group, obvious inflammation occurred in the lung tissue of mice in the model group. The lung index, the content of MMP-9, and the value of MMP-9/TIMP-1 increased significantly in the model group (P < 0.01) , while the content of TIMP-1 was not significantly different (P > 0.05). Compared with the model group, the content of MMP-9 in the low and middle dose Dureping Injection groups, and the positive control group was significantly lowered (P < 0.01). The content of TIMP-1 in the low, middle, and high dose Dureping Injection groups, as well as the positive control group significantly increased (P < 0.01) and the value of MMP-9/TIMP-1 decreased (P < 0.01). CONCLUSION: Dureping Injection could alleviate the inflammatory injury of the lung tissue through decreasing the content of MMP-9, elevating the content of TIMP-1 in the lung tissue, and regulating the value of MMP-9/TIMP-1 of mice with pneumonia of influenza virus infection, thus alleviating the inflammatory injury of the lung tissue.