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Moreover, it is presumed that AxD pathogenesis occur due to interactions with neurons and other glial cells, as well as the microenvironment in tissues. Research strategies based on these perspectives will help us understand AxD pathology better and may lead to the elucidation of disease modifiers and clinical diversity.Sandhoff disease (SD) is a genetic disorder caused by a mutation in the β-hexosaminidase B (HexB) gene in humans. This results in the massive accumulation of GM2 gangliosides in the nervous system, causing progressive neurodegeneration. The symptoms of SD include muscle weakness, seizures, and mental illness;along with loss of muscle coordination, vision, and hearing. In the most severe form, the onset begins during early infancy, and death usually occurs within 3-5 years of age. The established animal model, Hexb-deficient (Hexb-/-) mouse, shows abnormalities that resemble the severe phenotype found in human infants. We have previously reported that activated microglia causes astrogliosis in Hexb-/- mouse at the early stage of development that can be ameliorated via immunosuppression. Moreover, within the cerebral cortices of Hexb-/- mouse, reactive astrocytes were found to express adenosine A2A receptors in later inflammatory phases. Inhibiting this receptor with istradefylline decreases the number of activated microglial cells and inflammatory cytokines/chemokines. Thus, we underline the importance of the astrocytic A2A receptor as a sensor, in regulating microglial activation in the late phase of inflammation.Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), and is designated as an intractable disease in Japan. It is characterized by dissemination of plaque-like sclerosis in space and time, accompanied with various symptoms corresponding to the CNS lesion site. Typically, neurological symptoms chronically progress accompanied with relapses and remissions, and there is still no curative therapy. A number of studies using MS specimen and the animal MS model experimental autoimmune encephalomyelitis (EAE) have shown that MS is an autoimmune disease that targets myelin sheath in the CNS. Autoreactive T cells and B cells play a central role in pathogenesis of MS. MS comprise relapsing-remitting MS and progressive MS, the latter accumulates clinical disability without relapse. Based on the importance of adaptive immunity, various disease-modifying drugs have been developed to treat relapsing-remitting MS. On the other hand, an effective treatment for progressive MS has not yet been established. Increasing evidence have been recognized glial cells as key components of MS immunopathology, in addition to innate immunity and adaptive immunity. However, molecular mechanisms of crosstalk between immune cells, glial cells and neurons remain to be elucidated. Here, we review MS pathology and recent advances in the disease-modifying therapy that efficiently reduce disease activity in relapsing-remitting MS and introduce an update of recent evidence that astrocyte is involved in the MS pathology with including our research analyzed in mouse EAE model.Microglia originating from yolk sac exert various functions to maintain the homeostasis in the brain, and their functional breakdown appears to be involved in the pathophysiology of various neurological diseases. In this review article, loss of homeostatic microglia and new therapeutic approaches for rare neurological disorders are discussed. ASLP (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) known as a primary microgliopathy is an adult-onset leukoencephalopathy caused by CSF1R mutation. CSF1 receptor encoded by CSF1R plays an important role in the function of microglia. In brain of ALSP patients, homeostatic microglia are significantly reduced. The biallelic mutations for CSF1R cause childhood-onset severe phenotype and elimination of microglia from the brain parenchyma. Since microglia also almost disappear in CSF1R-deficient mice and rats, CSF1R deficiency and loss of microglia appear to be tightly associated across species. Based on the underlying mechanism of homeostatic microglia loss, novel approaches using cell transplantation of normal microglia-like cells have been attempted. Transplantation of wild-type bone marrow cells into Csf1r-/- mice results in replacement by donor-derived microglial-like cells in the recipient’s brain. The concept of “microglial niche” may explain the rationale behind the microglial cell transplantation in disease condition(s). Hematopoietic stem cell transplantation (HSCT) has been attempted in 4 patients with ALSP. GSK3368715 order Beneficial effects by showing stabilization of the disease course have been observed. Although the effectiveness of HSCT for ALSP patients warrants further investigation, the approach of cell transplantation that replaces ruptured homeostatic microglia with normal microglia-like cells seems to be promising.Schizophrenia is characterized by positive symptoms, negative symptoms and cognitive dysfunction. Although the abnormal neuronal development, impaired synaptic functions and impaired neural circuit functions are suggested to be the causes of psychiatric disorders, the molecular and cellular etiology of schizophrenia remains largely unclear. iPS-related technologies can be powerful for not only understanding the molecular and cellular etiology of schizophrenia but also drug discovery research. In 2011, the first iPS cells derived from patients with schizophrenia harboring a DISC1 mutation were generated. Subsequently, many iPS cells from patients with schizophrenia were established for understanding the molecular and cellular disease phenotypes of the differentiated neuronal cells. For replicating disease phenotypes with iPSC-derived neuronal cells, it is important to develop the differentiation strategies for generating cell-type specific cultures of various types of neurons, astrocytes and oligodendrocytes. Especially, scalable cultures of iPSC-derived neuronal cells are valuable platforms for drug discovery research. In this review, the focus has been made on the iPSC differentiation technology, pharmacological and drug discovery studies with iPSC-derived neurons from patients with schizophrenia. Continued advancement of the iPSC-related technologies and research will help the success in central nervous system drug discovery and development.