Metabolic waste clearance is essential to maintain body homeostasis, in which the lymphatic system plays a vital role. Conversely, in recent years, studies have identified the glial–lymphatic system in the brain, which primarily comprises the inflow of fluid along the para-arterial space. Aquaporin-4 mediates the convection of interstitial fluid in the brain and outflow along the paravenous space. β-Amyloid deposition is a characteristic pathological change in Alzheimer’s disease, and some studies have found that the glial–lymphatic system plays an important role in its clearance. Thus, the glial–lymphatic system may influence Alzheimer’s disease severity and outcome; therefore, this review summarizes the current and available research on the glial–lymphatic system and Alzheimer’s disease.
Aquaporin 4 (AQP4) is the most abundant aquaporin type in the brain. It is mainly expressed in the perivascular end feet of astrocytes. A large number of studies have shown that AQP4 is involved in the formation and elimination of brain edema in intracerebral hemorrhage, and plays important roles in the maintenance of the integrity of blood-brain barrier, secondary neuroinflammation, and apoptosis after intracerebral hemorrhage. More and more studies focus on the roles and mechanisms of AQP4 in intracerebral hemorrhage, however, the results are not completely consistent. This article reviews the roles and mechanisms of AQP4 in intracerebral hemorrhage
Key words:
Cerebral Hemorrhage; Aquaporin 4; Blood-Brain Barrier; Brain Edema; Inflammation
The central nervous system inflammatory response plays an important role in the pathogenesis of AD. Pro-inflammatory cytokines can induce inflammatory reactions in the body, enhance the neurotoxic effects caused by Aβ, promote the pathogenesis of AD and anti-inflammatory factors can down-regulate the inflammatory response, play a protective role and promote the reconstruction of damaged tissue. However, due to the existence of genetic polymorphisms, the influence of inflammatory factors on AD is complicated, especially in different population groups. Studing and clarifying the relationship between gene polymorphisms of inflammatory factors and and the pathogenesis of AD will promote the study of the mechanism of AD and provide a new method for the treatment of AD. Therefore, this article mainly reviews this.
Key words:
Alzheimer's disease; Inflammatory cytokines; Gene polymorphisms
Inflammatory responses contribute to the pathogenesis of various neurological diseases, and microglia plays an important role in the process. Activated microglia can differentiate into the pro-inflammatory, tissue-damaging M1 phenotype or the anti-inflammatory, tissue-repairing M2 phenotype. Regulating microglia differentiation, hence limiting a harmful response, might help improve the prognosis of inflammation-related nervous system diseases. The present study aimed 1. to observe the anti-inflammatory effect of lipoxin A4 (LXA4) on the inflammatory response associated to lipopolysaccharide (LPS)-induced microglia activation, 2. to clarify that LXA4 modulates the activation and differentiation of microglia induced by LPS stimulation, 3. to determine whether LXA4 regulates the activation and differentiation of microglia through the Notch signaling pathway, 4. to provide a foundation for the use of LXA4 for the treatment of inflammatory related neurological diseases. To construct a model of cellular inflammation, immortalized murine BV2 microglia cells were provided 200 ng/ml LPS. To measure the mRNA and protein levels of inflammatory factors (interleukin [IL]-1β, IL-10, and tumor necrosis factor [TNF]-α) and M1 and M2 microglia markers (inducible nitric oxide synthase [iNOS], cluster of differentiation [CD]32, arginase [Arg]1, and CD206), we performed quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), immunofluorescence, or flow cytometry. To determine the mRNA and protein levels of Notch signaling components (Notch1, Hes1, and Hes5), we performed qRT-PCR and western blot. LXA4 inhibits the expression of Notch1 and Hes1 associated with M1 type microglial differentiation and decreases the M1 type microglia marker iNOS and related inflammatory factors IL-1β and TNF-α. Moreover, LXA4 upregulates the expression of the M2-associated Hes5, as well as the expression of the M2 microglia marker Arg1 and the associated inflammatory factor IL-10. These effects are blocked by the administration of the γ-secretase inhibitor DAPT, a specific blocker of the Notch signaling pathway. LXA4 inhibits the microglia activation induced by LPS and the differentiation into M1 type with pro-inflammatory effect, while promoting the differentiation to M2 type with anti-inflammatory effect. LXA4 downregulates the inflammatory mediators IL-1β, TNF-α, and iNOS, while upregulating the anti-inflammatory mediator IL-10, which acts through the Notch signaling pathway.
Objective
To observe the effect and molecular mechanism of lipopolysaccharide (LPS) on activation and differentiation of microglia (MG) cells.
Methods
Routinely in vitro cultured BV2 microglia cells were divided into control group and LPS group: BV2 microglia cells in the LPS group were treated with 200 ng/mL LPS; cells in the control group were added the same amount of medium. Six h after treatment, real-time quantitative (qRT)-PCR and enzyme-linked immunosorbent assay (ELISA) were used to detect the inflammatory factors, interleukin (IL)-1β and tumor necrosis factor (TNF)-α mRNA and protein expressions in supernatant of cell culture medium. The iNOS, CD32, Arg1 and CD206 mRNA and protein expressions were detected by qRT-PCR and immunofluorescence, respectively. The mRNA and protein expressions of Notch1, Hes1 and Hes5 were detected by qRT-PCR and Western blotting.
Results
After LPS stimulation, BV2 microglia cells were activated and the morphological changes were observed. The IL-1β and TNF-α protein and mRNA expressions in the LPS group were significantly increased as compared with those in the control group (P 0.05). The Notch1 and Hes1 mRNA and protein expressions in the LPS group were significantly increased as compared with those in the control group (P 0.05).
Conclusion
LPS activates MG cells, which may regulate the differentiation of MG cells into M1 through Notch signaling pathway and promote inflammatory response; therefore, Notch signaling pathway may be a target for regulating MG cells differentiation and reducing inflammatory damage.
Key words:
Inflammatory response; Microglia cell; Cell differentiation; Lipopolysaccharide; Notch signaling pathway
Alzheimer′s disease (AD) is a neurodegenerative disease of the central nervous system that starts slowly and progressively leads to cognitive impairment. Clusterin, as an apolipoprotein, is usually widely expressed in mammalian brain tissue. In previous studies, below theories have been demonstrated: clusterin influences the aggregation, clearance and neurotoxicity of β-amyloid; compared to healthy people, AD patients show higher clusterin level in plasma and cerebrospinal fluid; the polymorphisms of clusterin gene encoding clusterin can enhance the incidence risk of AD. In addition, regulating the expression of clusterin in AD animals model has certain therapeutic effect on AD. Further investigating intrinsic relationship between clusterin and AD will help clarify the pathogenesis and establish a new therapeutic target of AD thus contributing to the prevention of Alzheimer′s disease.
Key words:
Clusterin; Alzheimer disease; Apolipoproteins J; β-Amyloid
The aim has been to determine whether the supernatants of mesenchymal stem cells (MSCs) transfected with adenovirus carrying human heme oxygenase-1 (hHO-1) gene protect cardiomyocytes from ischemic injury. We have found that hHO-1 infected MSCs (hHO-1-MSCs) increased expression of hHO-1 protein. Apoptosis of cultured hHO-1-MSCs exposed to hypoxia was suppressed. Several cytokines, including HGF, bFGF, TGF-beta, VEGF and IL-1beta, were produced by hHO-1-MSCs, some being significantly enhanced under hypoxia stimulation. Meanwhile, those cytokines reduced caspase-3 level and activity in cultured adult rat ventricular cardiomyocytes (ARVCs) exposed to hypoxia. Supernatants obtained from hHO-1-MSCs improved left ventricular function, limited myocardial infarct size, increased microvessel density, and inhibited apoptosis of cardiomyocytes in rat myocardial infarction. It can be concluded hHO-1-modified MSCs prevent myocardial cell injury via secretion of paracrine-acting mediators.
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