Inhibition of GM3 Synthase Attenuates Neuropathology of Niemann-Pick Disease Type C by Affecting Sphingolipid Metabolism

In several lysosomal storage disorders, including Niemann-Pick disease Type C (NP-C), sphingolipids, including glycosphingolipids, particularly gangliosides, are the predominant storage materials in the brain, raising the possibility that accumulation of these lipids may be involved in the NP-C neurodegenerative process. However, correlation of these accumulations and NP-C neuropathology has not been fully characterized. Here we derived NP-C mice with complete and partial deletion of the Siat9 (encoding GM3 synthase) gene in order to investigate the role of ganglioside in NP-C pathogenesis. According to our results, NPC mice with homozygotic deletion of GM3 synthase exhibited an enhanced neuropathological phenotype and died significantly earlier than NP-C mice. Notably, in contrast to complete depletion, NP-C mice with partial deletion of the GM3 synthase gene showed ameliorated NP-C neuropathology, including motor disability, demyelination, and abnormal accumulation of cholesterol and sphingolipids. These findings indicate the crucial role of GM3 synthesis in the NP-C phenotype and progression of CNS pathologic abnormality, suggesting that well-controlled inhibition of GM3 synthesis could be used as a therapeutic strategy.     

Defective Self-Renewal and Differentiation of GBA-Deficient Neural Stem Cells Can Be Restored By Macrophage Colony-Stimulating Factor

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the glucocerebrosidase gene (GBA), which encodes the lysosomal enzyme glucosylceramidase (GCase). Deficiency in GCase leads to characteristic visceral pathology and lethal neurological manifestations in some patients. Investigations into neurogenesis have suggested that neurodegenerative disorders, such as GD, could be overcome or at least ameliorated by the generation of new neurons. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are potential candidates for use in the treatment of neurodegenerative disorders because of their ability to promote neurogenesis. Our objective was to examine the mechanism of neurogenesis by BM-MSCs in GD. We found that neural stem cells (NSCs) derived from a neuronopathic GD model exhibited decreased ability for self-renewal and neuronal differentiation. Co-culture of GBA-deficient NSCs with BM-MSCs resulted in an enhanced capacity for self-renewal, and an increased ability for differentiation into neurons or oligodendrocytes. Enhanced proliferation and neuronal differentiation of GBA-deficient NSCs was associated with elevated release of macrophage colony-stimulating factor (M-CSF) from BM-MSCs. Our findings suggest that soluble M-CSF derived from BM-MSCs can modulate GBA-deficient NSCs, resulting in their improved proliferation and neuronal differentiation.     

AMD3100 improves ovariectomy-induced osteoporosis in mice by facilitating mobilization of hematopoietic stem/progenitor cells

Inhibition of an increase of osteoclasts has become the most important treatment for osteoporosis. The CXCR4 antagonist, AMD3100, plays an important role in the mobilization of osteoclast precursors within bone marrow (BM). However, the actual therapeutic impact of AMD3100 in osteoporosis has not yet been ascertained. Here we demonstrate the therapeutic effect of AMD3100 in the treatment of ovariectomy-induced osteoporosis in mice. We found that treatment with AMD3100 resulted in direct induction of release of SDF-1 from BM to blood and mobilization of hematopoietic stem/progenitor cells (HSPCs) in an osteoporosis model. AMD3100 prevented bone density loss after ovariectomy by mobilization of HSPCs, suggesting a therapeutic strategy to reduce the number of osteoclasts on bone surfaces. These findings support the hypothesis that treatment with AMD3100 can result in efficient mobilization of HSPCs into blood through direct blockade of the SDF-1/CXCR4 interaction in BM and can be considered as a potential new therapeutic intervention for osteoporosis. [BMB Reports 2014; 47(8): 439-444]     

A Novel and Selective p38 Mitogen-Activated Protein Kinase Inhibitor Attenuates LPS-Induced Neuroinflammation in BV2 Microglia and a Mouse Model

Neuroinflammation is an important pathological feature in neurodegenerative diseases. Accumulating evidence has suggested that neuroinflammation is mainly aggravated by activated microglia, which are macrophage like cells in the central nervous system. Therefore, the inhibition of microglial activation may be considered for treating neuroinflammatory diseases. p38 mitogen-activated protein kinase (MAPK) has been identified as a crucial enzyme with inflammatory roles in several immune cells, and its activation also relates to neuroinflammation. Considering the proinflammatory roles of p38 MAPK, its inhibitors can be potential therapeutic agents for neurodegenerative diseases relating to neuroinflammation initiated by microglia activation. This study was designed to evaluate whether NJK14047, a recently identified novel and selective p38 MAPK inhibitor, could modulate microglia-mediated neuroinflammation by utilizing lipopolysaccharide (LPS)-stimulated BV2 cells and an LPS-injected mice model. Our results showed that NJK14047 markedly reduced the production of nitric oxide and prostaglandin E₂ by downregulating the expression of various proinflammatory mediators such as nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α and interleukin-1β in LPS-induced BV2 microglia. Moreover, NJK14047 significantly reduced microglial activation in the brains of LPS-injected mice. Overall, these results suggest that NJK14047 significantly reduces neuroinflammation in cellular/vivo model and would be a therapeutic candidate for various neuroinflammatory diseases.     

Synergistic vasculogenic effects of AMD3100 and stromal-cell-derived factor-1α in vasa nervorum of the sciatic nerve of mice with diabetic peripheral neuropathy

Autologous endothelial progenitor cell (EPC) transplantation has been suggested as a potential therapeutic approach in diabetic neuropathy (DN). However, such treatment might be limited by safety concerns regarding possible unwanted proliferation or differentiation of the transplanted stem cells. An alternative approach is the stimulation of endogenous bone-marrow-derived EPC (BM-EPC) recruitment into ischemic lesions by the administration of stem cell mobilization agents or chemokines. We first tested the EPC mobilization effect of vascular endothelial growth factor (VEGF) and AMD3100 in a mouse model of diabetes and found that AMD3100 was effective as an EPC mobilization agent, whereas VEGF did not increase circulating EPCs in these animals. Because recent studies have suggested that deceased local expression of stromal-cell-derived factor (SDF)-1α in diabetes is the main cause of defective EPC migration, AMD3100 was administrated systemically to stimulate EPC mobilization and SDF-1α was injected locally to enhance its migration into the streptozotocin-induced DN mice model. This combined therapy increased local expression levels of vasculogenesis-associated factors and newly formed endothelial cells in the sciatic nerve, resulting in the restoration of the sciatic vasa nervorum. The treatment also improved the impaired conduction velocity of the sciatic nerve in DN mice. Thus, AMD3100 might be an effective EPC mobilization agent in diabetes, with local SDF-1α injection synergistically increasing vascularity in diabetic nerves. This represents a novel potential therapeutic option for DN patients.     

Adipose tissue-derived stem cells rescue Purkinje neurons and alleviate inflammatory responses in Niemann-Pick disease type C mice

Adult stem cells offer special therapeutic prospects because they can be isolated for autologous transplantation, expanded ex vivo, and differentiated into various cell types. We previously reported that bone marrow-derived mesenchymal stem cells improve neurological deficits in neurodegenerative disease animal models. However, the efficacy of adipose tissue-derived stem cells (ADSCs) transplantation in similar models remains unknown. Herein, we demonstrate that ADSCs, when transplanted into Niemann-Pick disease type C (NP-C) mouse cerebellum, elicit rescue of Purkinje neurons and restoration of motor coordination together with alleviation of inflammatory responses as verified by immunohistochemistry and real-time PCR using glial fibrillary acidic protein (GFAP), F4/80, IL-1β, IL-6, and TNF-α. Most importantly, ADSCs enhance electrically active Purkinje neurons with functional synaptic formation after transplantation in NP-C disease model mice. This report demonstrates for the first time that ADSCs can rescue imperiled Purkinje neurons and alleviate the inflammatory response in NP-C disease model mice, thereby signifying the therapeutic potential of ADSCs for neurodegenerative diseases.     

Staphylococcus epidermidis WF2R11 Suppresses PM2.5-Mediated Activation of the Aryl Hydrocarbon Receptor in HaCaT Keratinocytes

Probiotics and Antimicrobial Proteins - The skin supports a diverse microbiome whose imbalance is related to skin inflammation and diseases. Exposure to fine particulate matter (PM2.5), a major air...     

Role of neuropeptide Y in the bone marrow hematopoietic stem cell microenvironment

The sympathetic nervous system (SNS) or neurotransmitters in the bone marrow microenvironment has been known to regulate hematopoietic stem cell (HSC) functions such as self-renewal, proliferation and differentiation. However, the specific role of neuropeptide Y (NPY) in this process remains relatively unexplored. In this study, we demonstrated that NPY deficient mice have significantly reduced HSC numbers and impaired bone marrow regeneration due to apoptotic destruction of SNS fibers and/or endothelial cells. Moreover, NPY treatment prevented bone marrow impairments in a mouse model of chemotherapy-induced SNS injury, while conditional knockout mice lacking the Y1 receptor in macrophages did not restore bone marrow dysfunction in spite of NPY injection. Transforming growth factor-beta (TGF-β) secreted by NPY-mediated Y1 receptor stimulation in macrophages plays a key role in neuroprotection and HSC survival in the bone marrow. Therefore, this study reveals a new role of NPY in bone marrow HSC microenvironment, and provides an insight into the therapeutic application of this neuropeptide. [BMB Reports 2015; 48(12): 645-646]     

MEGF10 functions as a receptor for the uptake of amyloid-β

MEGF10 is predominantly expressed in the brain and known to function as a phagocytic receptor. Here, we provide evidence that MEGF10 is involved in the uptake of amyloid-β peptide (Aβ42) in the brain. Overexpression of MEGF10 dramatically increased Aβ42 uptake in Hela cells. Knockdown of endogenous MEGF10 expression significantly decreased Aβ42 uptake in N2A neuroblastoma cells. MEGF10-mediated Aβ uptake is mostly dependent on lipid raft endocytosis pathway. Furthermore, site-directed mutagenesis revealed that the conserved cytoplasmic NPxY and YxxØ motifs are crucial for MEGF10-mediated uptake of Aβ42 peptide. Thus, the identification of the MEGF10 as a functional receptor that mediates the uptake of amyloid-β peptide will help elucidate the molecular mechanisms of amlyoid-β clearance in Alzheimer’s disease.

Structured summary

MINT-7993537: ctxB (uniprotkb:P01556) and Abeta (uniprotkb:P05067) colocalize (MI:0403) by fluorescence microscopy (MI:0416)     

The blood cerebrospinal fluid barrier orchestrates immunosurveillance,immunoprotection, and immunopathology in the central nervous system

Once characterized as an immune privileged area, recent scientific advances have demonstrated that the central nervous system (CNS) is both immunologically active and a specialized site. The anatomical and cellular features of the brain barriers, the glia limitans, and other superficial coverings of the CNS endow the brain with specificity for immune cell entry and other macro- and micro-elements to the brain. Cellular trafficking via barriers comprised of tightly junctioned non-fenestrated endothelium or tightly regulated fenestrated epithelium results in different phenotypic and cellular changes in the brain, that is, inflammatory versus regulatory changes. Based on emerging evidence, we described the unique ability of the blood cerebrospinal fluid barrier (BCSFB) to recruit, skew, and suppress immune cells. Additionally, we sum up the current knowledge on both cellular and molecular mechanisms governed by the choroid plexus and the cerebrospinal fluid at the BCSFB for immunosurveillance, immunoprotection, and immunopathology.