Published papers

Multiple sclerosis(MS) is an inflammatory demyelinating disease of the central nervous system with yet undetermined etiology. The incidence of MS is rapidly rising in Japan, and in addition to four already-approved disease-modifying therapies (DMTs), namely interferon β1b, interferonβ1a, fingolimod and natalizumab, several new DMTs are currently under clinical trials. In this article, emerging DMTs such as alemtuzumab, dimethyl fumarate and teriflunomide as well as fampridine, a novel symptomatic treatment for gait disturbance, and anti-LINGO-1 monoclonal antibody, a possible candidate for future remyelination therapy, will be reviewed. Future treatment strategies such as induction therapy and combined therapy for MS will also be discussed.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), in which inflammation develops upon leukocyte invasion into the CNS via the blood-brain barrier. α4-Integrin is an important cell adhesion molecule involved in the penetration process. Natalizumab is an α4-integrin-targeting monoclonal antibody that was recently approved for use as a disease-modifying therapy for MS in Japan. In this article, the mechanism of action, efficacy, and side effects of natalizumab will be reviewed.

A recent article published in Nature presents intriguing data suggesting that the activation of neuronal nuclear factor-κB (NF-κB) in the mediobasal hypothalamus (MBH) causes systemic aging through reduced secretion of gonadotropin-releasing hormone, an anti-aging hormone. Microglial inflammation in MBH also seems to induce neuronal NF-κB. These results raise the possibility that neuroinflammation orchestrates systemic aging. © 2013 Japanese Society for Neuroimmunology.

Spontaneous remyelination occurs in many early multiple sclerosis (MS) patients, however its capacity decreases as the disease becomes chronic. Even in those chronic MS patients, an enough number of oligodendrocyte precursor cells (OPCs) are preserved within the demyelinated lesions, suggesting that the differentiation arrest of oligodendroglial cells underlies the remyelination failure in chronic MS. We have previously reported that TIP30, a factor inhibiting nucleocytoplasmic transport within the cell, is responsible for the differentiation arrest in MS lesions. Overexpression of TIP30 in the preserved OPCs in MS lesions results in the failure of nuclear translocation of transcription factors necessary for oligodendroglial differentiation. Therefore, anti-TIP30 therapy to regain the nuclear access within the OPCs is necessary for sufficient remyelination in chronic MS patients. Moreover, inflammatory conditions surrounding OPCs may be involved in the efficient remyelination in early MS lesions, alternative stimulatory factor may therefore be mandatory to induce OPC differentiation into oligodendrocytes within the chronic lesion. We have previously reported that targeting FcRy protein on OPCs may stimulate their differentiation and consequently remyelination in the chronic lesions. A timely collaboration of these two approaches may be required for successful remyelination and neurological recovery in chronic MS patients.

Myelin is a multi-layered membranous lipid insulator surrounding axons that allows the rapid conduction of neuronal impulses. In the central nervous system (CNS), myelin is produced by oligodendrocytes. During development, morphologically immature oligodendrocyte precursor cells (OPCs) arise from neural stem cells before differentiating into myelinating oligodendrocytes shortly after birth. Fyn tyrosine kinase (Fyn) has been shown to play a central role during OPC differentiation, including inducing morphological changes in the cells and initiating the expression of myelin basic protein (MBP), a major structural protein required for the compaction of myelin sheaths. Recently, we have shown that signaling via the γ chain of immunoglobulin Fc receptors (FcRγ) induces the Fyn-MBP cascade and promotes the morphological differentiation of OPCs. The protein tyrosine phosphatases that are responsible for the positive regulation of Fyn tyrosine kinase activity during this cascade, however, remained unknown. Here we report that a protein tyrosine phosphatase, CD45, is involved in this process. Fyn co-immunoprecipitated with CD45 from differentiating wild-type OPCs in vitro, while CD45-deficient OPCs failed to differentiate. Additionally, dysmyelination was observed in CD45-deficient mice in vivo. Our findings suggest that CD45 is a key phosphatase involved in OPC differentiation and provide a preliminary explanation for the previously reported CD45 mutations observed in some multiple sclerosis (MS) patients. © 2005 Elsevier Ireland Ltd. All rights reserved.

We report studies on the mechanism of action of bisphenol A (BPA) on the differentiation of oligodendrocyte precursor cells (OPCs). Our results show that: (1) BPA inhibits the differentiation of OPCs induced by exposure to thyroid hormone (T3 ). (2) The effect is mediated through various mechanisms via the thyroid hormone receptor (TRβ1) which is considered to be responsible for OPC differentiation. (3) The action of BPA on OPC differentiation does not involve the FcRγ -Fyn-myelin basic protein (MBP) cascade as an inducer of OPC differentiation nor does it suppress CREB phosphorylation, which is considered to be induced by the T3 -TR complex. (4) The presence of MBP isoforms (21.5, 18.5, 17.0 and 14.0 kDa) was detected in OPCs, and the expression of exon 2-containing isoforms (i.e. 17.0 and 21.5 kDa) was upregulated upon treatment with T3 . In contrast, expression of MBP was inhibited by BPA. Copyright © 2004 S. Karger AG, Basel.

While the exact aetiology of Alzheimer's disease (AD) is unknown, distinct genetic mutations have been identified for the rare cases of familial AD (FAD). V642I mutation in amyloid precursor protein (APP) co-segregates with FAD with perfect penetration, and the clinicopathological characteristics of patients with this mutation resemble that of sporadic AD. To examine the pathogenic process of this FAD-linked trait in vivo, we produced a mouse with the corresponding point mutation in the APP gene using homologous recombination and Cre-loxP site-specific recombination ('knock-in' technique). Mice with the heterozygous V642I-APP allele most precisely reflected the genotype of humans bearing this mutation. For the observation period of 2.5 years the mutants stayed apparently indistinguishable from the wild-type littermates. However, behavioural analysis revealed significantly deteriorated long-term memory in mutants when examined for the retention of spatial attention. Interestingly, acquisition of spatial memory was slightly affected but short-term working memory was not deteriorated at all. Histological examination was negative for formation of neuritic plaques or neurofibrillary tangles, whereas the relative amount of longer form of β-amyloid species Aβ42(43) was significantly increased against that of the shorter form (Aβ40) in the mutant brain homogenates. We conclude that a V642I-APP mutant allele in aged mice confers functional components, but not organic components, of the AD-related phenotype that are observed in the early stage of AD. This V642I-APP knock-in mutant line may serve as a model to study the early pathogenic processes of AD in vivo and to develop therapeutics for this stage.

Dramatic changes in morphology and myelin protein expression take place during the differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes. Fyn tyrosine kinase was reported to play a central role in the differentiation process. Molecules that could induce Fyn signaling have not been studied. Such molecules are promising therapeutic targets in demyelinating diseases. We provide evidence that the common γ chain of immunoglobulin Fc receptors (FcRγ) is expressed in OPCs and has a role in triggering Fyn signaling. FcRγ cross-linking by immunoglobulin G on OPCs promotes the activation of Fyn signaling and induces rapid morphological differentiation with upregulation of myelin basic protein (MBP) expression levels. Mice deficient in FcRγ are hypomyelinated, and a significant reduction in MBP content is evident. Our findings indicate that the FcRγ-Fyn-MBP cascade is pivotal during the differentiation of OPCs into myelinating oligodendrocytes, revealing an unexpected involvement of immunological molecules.

Recent in vitro study showed that astrocytes induce oli-godendrocyte processes to adhere to axons. However, the role of astrocytes in myelination in vivo remains unknown. We have, therefore, conducted a study to clarify the possible involvement of astrocytes during the initial myelination process. In newborn mice, the expression of glial fibrillary acidic protein (GFAP), a marker for astrocytes, was restricted to a few fibrous architectures in the subventricular zone (SVZ), but we did not observe any GFAP-positive astrocytes. Prior to the onset of myelination, GFAP became transiently expressed in the cells with radial fibers elongating from the SVZ to the pia of cerebral cortex, and myelin-associated glycoprotein (MAG)-positive premyelinating oligodendrocytes appeared as neighbors to them, with the processes attaching to radial fibers, but not to axons. These GFAP-positive "radial" cells lost their fibrous architecture and became typical GFAP-positive astrocytes at about 10 days postnatally, when myelination set in, indicating that the disappearance of radial fibers coordinates with the initiation of myelination. From these results, we propose that premyelinating oligodendrocytes are in contact with radial fibers rather than axons and that the cytoarchitectural transformation of radial fibers into astrocytes is involved substantially in controlling the onset of initial myelination. Our proposal was further confirmed by GFAP-deficient mice, in which the disappearance of these radial fibers and the initiation of myelination were delayed in parallel. Our findings together suggest that myelination in vivo is in concert with astrocytic differentiation, involving radial fibers therein, rather than being a mere axon-oligodendrocyte interaction. © 2003 Wiley-Liss, Inc.

Deletions in the DAP12 gene in humans result in Nasu-Hakola disease, characterized by a combination of bone fractures and psychotic symptoms similar to schizophrenia, rapidly progressing to presenile dementia. However, it is not known why these disorders develop upon deficiency in DAP12, an immunoreceptor signal activator protein initially identified in the immune system. Here we show that DAP12-deficient (DAP12-/-) mice develop an increased bone mass (osteopetrosis) and a reduction of myelin (hypomyelinosis) accentuated in the thalamus. In vitro osteoclast induction from DAP12-/- bone marrow cells yielded immature cells with attenuated bone resorption activity. Moreover, immature oligodendrocytes were arrested in the vicinity of the thalamus, suggesting that the primary defects in DAP12-/- mice are the developmental arrest of osteoclasts and oligodendrocytes. In addition, the mutant mice also showed synaptic degeneration, impaired prepulse inhibition, which is commonly observed in several neuropsychiatric diseases in humans including schizophrenia, and aberrant electrophysiological profiles in the thalami. These results provide a molecular basis for a unique combination of skeletal and psychotic characteristics of Nasu-Hakola disease as well as for schizophrenia and presenile dementia.

Recent advances in neuro-immunology are beginning to elucidate several essential roles of the humoral immunity in both repair and pathogenesis of central nervous system diseases. Immunoglobulin M (IgM) was reported to accelerate the rate of remyelination in a demyelinating disease model, while intrathecal IgM synthesis was shown to predict a more worse disease course in a human demyelinating disease, multiple sclerosis. Molecular mechanisms for either of these IgM functions remain to be studied. Here we report that a recently-found Fc receptor for IgM, namely Fcα/μR, is expressed in oligodendrocytes, their precursor cells, and myelin. These expressions were confirmed by immunocytochemistry of cultured cells, Western blot analysis of myelin fractions, and also by immunohistochemistry of mouse forebrains at different ages. Our findings suggest a possible direct interaction between IgM and Fcα/μR expressed in oligodendrocytes and myelin. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

Myelin-associated glycoprotein (MAG) has currently been proposed to be a possible igniter of myelination in the central nervous system. We propose here that myelin basic protein (MBP) is prerequisite, which is more diffusely expressed than MAG in early stages of myelination. MBP-deficient mice show significant reduction of MAG-positive immature oligodendroglia at early stages of myelination, although significant increase of such cells is noted in the adult. MBP/Fyn-double deficient adult mice also show moderate increase of the same type of immature glia, but to a lesser degree than MBP-deficiency alone. The present study suggests that MBP is required for the regulation of MAG expression in oligodendroglia, involving Fyn therein. We discuss the possibility that hitherto unknown molecule, not MAG, may be in responsible for the ignition of the myelination. © 2001 Published by Elsevier Science Ireland Ltd.