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Background: Neuroinflammation has been widely accepted as a cause of the degenerative process. Increasing interest has been devoted to developing intervening therapeutics for preventing neuroinflammation in Parkinson's disease (PD). It is well known that virus infections, including DNA viruses, are associated with an increased risk of PD. In addition, damaged or dying dopaminergic neurons can release dsDNA during PD progression. However, the role of cGAS, a cytosolic dsDNA sensor, in PD progression remains unclear. Methods: Adult male wild‐type mice and age‐matched male cGAS knockout (cGas−/−) mice were treated with MPTP to induce neurotoxic PD model, and then behavioral tests, immunohistochemistry, and ELISA were conducted to compare disease phenotype. Chimeric mice were reconstituted to explore the effects of cGAS deficiency in peripheral immune cells or CNS resident cells on MPTP‐induced toxicity. RNA sequencing was used to dissect the mechanistic role of microglial cGAS in MPTP‐induced toxicity. cGAS inhibitor administration was conducted to study whether GAS may serve as a therapeutic target. Results: We observed that the cGAS‐STING pathway was activated during neuroinflammation in MPTP mouse models of PD. cGAS deficiency in microglia, but not peripheral immune cells, controlled neuroinflammation and neurotoxicity induced by MPTP. Mechanistically, microglial cGAS ablation alleviated the neuronal dysfunction and inflammatory response in astrocytes and microglia by inhibiting antiviral inflammatory signaling. Additionally, the administration of cGAS inhibitors conferred the mice neuroprotection during MPTP exposure. Conclusions: Collectively, these findings demonstrate microglial cGAS promote neuroinflammation and neurodegeneration during the progression of MPTP‐induced PD mouse models and suggest cGAS may serve as a therapeutic target for PD patients. Limitations of the Study: Although we demonstrated that cGAS promotes the progression of MPTP‐induced PD, this study has limitations. We identified that cGAS in microglia accelerate disease progression of PD by using bone marrow chimeric experiments and analyzing cGAS expression in CNS cells, but evidence would be more straightforward if conditional knockout mice were used. This study contributed to the knowledge of the role of the cGAS pathway in PD pathogenesis; nevertheless, trying more PD animal models in the future will help us to understand the disease progression deeper and explore possible treatments. [ABSTRACT FROM AUTHOR]

Human enterovirus 71 (EV71) causes hand, foot and mouth disease in children under 6 years of age, and the neurological complications of this virus can lead to death. Until now, no vaccines or drugs have been available for the clinical control of this epidemic. Macrophages can engulf pathogens and mediate a series of host immune responses that play a role in the defence against infectious diseases. Using immunohistochemistry, we observed the localizations of virus in muscle tissues of EV71-infected mice. The macrophages isolated from the adult mice could kill the virus gradually in vitro, as shown using quantitative real-time PCR (qRT-PCR) and virus titration. Co-localisation of lysosomes and virus within macrophages suggested that the lysosomes were possibly responsible for the phagocytosis of EV71. Activation of the macrophages in the peritoneal cavity of mice four days pre-infection reduced the mortality of mice upon lethal EV71 infection. The adoptive transfer of macrophages from adult mice inhibited virus replication in the muscle tissues of infected mice, and this was followed by a relief of symptoms and a significant reduction of mortality, which suggested that the adoptive transfer of macrophages from adult humans represents a potential strategy to treat EV71-infected patients. [ABSTRACT FROM AUTHOR]

Human PSGL-1 is a receptor for EV71 that facilitates EV71 entry and replication in mouse cells. We have evaluated the role of human PSGL-1 in EV71 infection in vivo using a transgenic mouse line. Expression of human PSGL-1 failed to enhance infectivity of clinical EV71 strains in mice; however, it promoted replication and symptom severity at an earlier stage in mice upon infection with a mouse-adapted EV71 strain. We therefore conclude that human PSGL-1 alone is not sufficient to modulate infection with the clinical EV71 strains of genotype C4 in mice. [ABSTRACT FROM AUTHOR]

Cytochrome P450 2E1 (CYP2E1) is an effective generator of reactive oxygen species. Marked expression of CYP2E1 occurs in the heart and it is known to be regulated in the course of progression of myocardial ischemia and cardiomyopathy. We provide evidence that the expression of CYP2E1 is strongly up-regulated in cTnT transgenic mice with dilated cardiomyopathy. Heart tissue-specific CYP2E1 transgenic mice were produced to study the effects of CYP2E1 overexpression on the heart. Increased mortality, chamber dilation and contractile dysfunction, as well as myocyte disarray, interstitial fibrosis, ultrastructural degeneration with myofibrillar disorganization and mitochondria damage, were observed in CYP2E1 transgenic mice and cTnT transgenic mice. In addition, levels of HO and malondialdehyde were increased and levels of glutathione and total antioxidant capability were strongly reduced in CYP2E1 transgenic mice and cTnT transgenic mice. Myocyte apoptosis was significantly increased by 19-fold in CYP2E1 transgenic mice and by 11-fold in cTnT transgenic mice, respectively, compared to wild-type mice. Mitochondrial-dependent apoptotic signal transduction events, such as cytochrome c release from mitochondria into the cytosol and the expression of cleaved (active) caspases 3 and 9, were significantly increased in CYP2E1 transgenic mice and cTnT transgenic mice. These results demonstrate that CYP2E1 over-expression produces apoptosis and that the up-regulation of CYP2E1 in cTnT transgenic mice also correlates with apoptosis in this model. Cytochrome P450 2E1 (CYP2E1) is an effective generator of reactive oxygen species. In this study we provided evidence that expression of CYP2E1 was strongly up-regulated in cTnT transgenic mice with dilated cardiomyopathy (DCM). The overexpression of CYP2E1 caused DCM phenotype, cardiac oxidative stress and myocyte apoptosis, all of which were similar to that in cTnT transgenic mice. [ABSTRACT FROM AUTHOR]

Abstract: Alzheimer's disease (AD) is a chronic neurodegenerative disease that causes a progressive loss in learning and memory capabilities and eventually results in dementia. The non-renewable nature of neurons in the central nervous system leads to the basic pathological changes that are related to the various behavioral and psychological symptoms of AD. Oligodendrocyte- and myelin-related neurite outgrowth inhibitors (NOIs) tend to hinder the regeneration of neurons. We designed a recombinant DNA vaccine composed of multiple specific inhibitory domains of NOIs. Vaccination induced effective antibodies against the specific domains in the sera of mice treated with a DNA primed-vaccinia virus boost regimen. The vaccine attenuated neuronal degeneration in the mouse brain and protected the model mice from behavioral deficits. Vaccination also decreased the formation of soluble Aβ oligomer and amyloid plaques in the co-transgenic mice brain. What's more, astrocytosis in brains of APP/PS1 co-transgenic mice was also relieved. The results suggested that immunotherapy with multiple specific domains of myelin- and oligodendrocyte-related NOIs may be a promising approach for Alzheimer's disease and other degenerative central nervous system diseases. [Copyright &y& Elsevier]

Abstract: Cardiotrophin-1 (CTF1) has been reported to act as a trophic factor for a few neurons, such as sensory, cholinergic, dopaminergic, motor and cortical neurons. Studies have indicated that CTF1 delays degenerative disease progression in motor neuron disease. However, little is known about the effects of CTF1 on degenerative disease in the brain. We have shown that expression of CTF1 is strongly down-regulated in the brain of the APPswe/PS1dE9 transgenic mouse model of Alzheimer's disease (AD). Transgenic mice with brain tissue-specific CTF1 expression alone or in combination with APPswe/PS1dE9 transgenic mice were produced to study the effects of CTF1 on AD. CTF1 expressing APPswe/PS1dE9 transgenic mice exhibited improvements in learning and memory, less severe abnormalities in locomotor activity, reduced scattered senile plaques and ameliorated disturbances of brain energy metabolism compared to APPswe/PS1dE9 transgenic mice. Furthermore, CTF1 inhibited the activity of glycogen synthase kinase-3β (GSK-3β) in SH-SY5Y cell line and in the brain tissues of APPswe/PS1dE9 transgenic mice. The transgenic expression of CTF1 compensated for the loss of CTF1 expression and brought about a marked improvement on cognitive functioning in the APPswe/PS1dE9 transgenic mouse model of Alzheimer's disease, suggesting that the inhibition of GSK-3β activity might play an important role. [Copyright &y& Elsevier]

Abstract: Enterovirus 71 (EV71) infections can usually cause epidemic hand, foot, and mouth disease (HFMD), and occasionally lead to aseptic meningitis, encephalitis, and polio-like illness. Skeletal muscles have been thought to be crucial for the pathogenesis of EV71-related diseases. However, little is known about the virulence of mouse muscle-adapted EV71. The EV71 0805 were subjected to four passages in the mouse muscle to generate a mouse-adapted EV71 strain of 0805a. In comparison with the parental EV71 0805, the mouse muscle-adapted EV71 0805a displayed stronger cytotoxicity against Rhabdomyosarcoma (RD) cells and more efficient replication in RD cells. Furthermore, infection with the EV71 0805a significantly inhibited the gain of body weight, accompanied by increased muscle virus load and multiple tissue distribution in the infected mouse. Histological examinations indicated that infection with the EV71 0805 did not cause obvious pathogenic lesions in mice, while infection with the muscle-adapted 0805a resulted in severe necrotizing myositis in the skeletal and cardio muscles, and intestinitis in mice on day 5 post infection. Further analysis revealed many mutations in different regions of the genome of mouse muscle-adapted virus. Collectively, these data demonstrated the mouse muscle-adapted EV71 0805a with increased virulence in mice. [Copyright &y& Elsevier]

Abstract: Recently, BACE1 expression was shown to be regulated by microRNAs, small endogenous RNA molecules that regulate protein expression through sequence-specific interaction with messenger RNA. Here, we showed that microRNA-29c (miR-29c), a miRNA that is enriched in the brain and highly expressed in the APPswe/PSΔE9 mouse lowers BACE1 protein in vitro and in transgenic miR-29c mice. In silico analysis identified two putative target sites in the BACE1 mRNA for the miR-29c family. We chose SH-SY5Y, HEK-293T cell lines and miR-29c transgenic mice for these studies to validate our hypothesis. Significantly, over-expression of miR-29c in SH-SY5Y, HEK-293T cell lines and miR-29c transgenic mice downregulated BACE1 protein levels. Our findings suggest that miR-29c may be an endogenous regulator of BACE1 protein expression. [Copyright &y& Elsevier]