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Publications (48)

  • Makoto Horiuchi · Lucas Smith · Izumi Maezawa · Lee-Way Jin
    [Show abstract] [Hide abstract] ABSTRACT: Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding MeCP2, an epigenetic modulator that binds the methyl CpG dinucleotide in target genes to regulate transcription. Previously we and others reported a role of microglia in the pathophysiology of RTT. Because microglia in the Mecp2 knockout (Mecp2KO) mouse model of RTT over-produce neurotoxic mediators glutamate and reactive oxygen species, we hypothesize that blocking neuron-microglia interaction by ablation of CX3CR1, a chemokine receptor expressed in microglia/myeloid cells mediating such interaction by pairing with its neuronal ligand CX3CL1, would ameliorate the RTT-like phenotype in Mecp2KO mice. Here we report that CX3CR1 ablation prolonged the lifespan of Mecp2KO mice from a median survival of 54.5 days to 74 days, and significantly improved the body weight gain, symptomatic scores, major respiratory parameters, and motor coordination and performance. CX3CR1 ablation rectified previously identified histological abnormalities in the Mecp2KO brain such as neuronal soma size in hippocampal CA2, and the number, soma size, and process complexity of microglia. Moreover, CX3CR1 ablation enhanced the neurotrophic action of microglia in Mecp2KO mice by producing higher amount of insulin-like growth factor 1. Our data support a role of myeloid cells/microglia in RTT and suggest a novel therapeutic approach for RTT by targeting CX3CR1 with specific antagonists or genetic downregulation.
    Article · Feb 2016 · Brain Behavior and Immunity
  • Yi-Je Chen · Hai M. Nguyen · Izumi Maezawa · [...] · Heike Wulff
    Article · Feb 2016 · Biophysical Journal
  • [Show abstract] [Hide abstract] ABSTRACT: Autism spectrum disorders (ASDs), including classic autism and various syndromic ASDs, are a diverse group of complex developmental disability characterized by social impairments, communication difficulties, and restricted, repetitive, and stereotyped patterns of behavior. As many as 1 in 80 children in the United States are affected by some form of ASDs, an alarming statistics. The core symptoms of autism are considered due to under-connectivity among the brain regions participating in cortical networks, a consequence of complex pathological gene–environmental interactions. Recent investigations on ASD susceptible genes and environmental risk factors such as exposure to environmental toxins, perinatal or postnatal infections, obstetric factors, and medications have provided greater clarity to the clinical and biological complexity of ASDs. This chapter provides a comprehensive review to illustrate that most genetic and environmental risks for ASDs cause dendritic abnormalities underlying brain under-connectivity. Rodent models harboring mutated ASD susceptible genes or exposed to environmental risk factors have helped delineate molecular pathways leading to autism-like dendritic abnormalities, and the findings can be further validated by human neuropathological studies. It is intriguing to consider dendritic abnormalities as main pathological substrates of autism; targeting specific molecular pathways driving such abnormalities could lead to realization of the ideal of providing “precision medicine” to autistic children. This review also illustrates that the immune system with its myriad of cells and mediators has a great impact on the developing brain, and our “microglia hypothesis” proposes that microglia play a pivotal role in mediating environmental and genetic effects on dendritic pathology in autism.
    Chapter · Jan 2016
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    Yi-Je Chen · Hai M Nguyen · Izumi Maezawa · [...] · Heike Wulff
    [Show abstract] [Hide abstract] ABSTRACT: Activated microglia/macrophages significantly contribute to the secondary inflammatory damage in ischemic stroke. Cultured neonatal microglia express the K+ channels Kv1.3 and KCa3.1, both of which have been reported to be involved in microglia-mediated neuronal killing, oxidative burst and cytokine production. However, it is questionable whether neonatal cultures accurately reflect the K+ channel expression of activated microglia in the adult brain. We here subjected mice to middle cerebral artery occlusion with eight days of reperfusion and patch-clamped acutely isolated microglia/macrophages. Microglia from the infarcted area exhibited higher densities of K+ currents with the biophysical and pharmacological properties of Kv1.3, KCa3.1 and Kir2.1 than microglia from non-infarcted control brains. Similarly, immunohistochemistry on human infarcts showed strong Kv1.3 and KCa3.1 immunoreactivity on activated microglia/macrophages. We next investigated the effect of genetic deletion and pharmacological blockade of KCa3.1 in reversible middle cerebral artery occlusion. KCa3.1−/− mice and wild-type mice treated with the KCa3.1 blocker TRAM-34 exhibited significantly smaller infarct areas on day-8 after middle cerebral artery occlusion and improved neurological deficit. Both manipulations reduced microglia/macrophage activation and brain cytokine levels. Our findings suggest KCa3.1 as a pharmacological target for ischemic stroke. Of potential, clinical relevance is that KCa3.1 blockade is still effective when initiated 12 h after the insult.
    Full-text Article · Nov 2015 · Journal of Cerebral Blood Flow & Metabolism
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    Hyun-Seok Hong · Izumi Maezawa · Jitka Petrlova · [...] · Lee-Way Jin
    [Show abstract] [Hide abstract] ABSTRACT: Amyloid-β (Aβ) protein causes neurotoxicity and its abnormal aggregation into amyloid is a pathological hallmark of Alzheimer's disease (AD). Cellular proteins able to interact with Aβ or its precursor, AβPP (amyloid-β protein precursor), may regulate Aβ production and neurotoxicity. We identified a brain-enriched type I transmembrane protein, tomoregulin (TR), that directly binds Aβ and Aβ oligomers (AβO). TR co-immunoprecipitated with Aβ and AβO in cultured cells and co-localized with amyloid plaques and intraneuronal Aβ in the 5xFAD AD mouse model. TR was also enriched in astrocytic processes reactive to amyloid plaques. Surface plasmon resonance spectroscopy studies showed that the extracellular domain of TR binds to AβO with a high affinity (KD = 76.8 nM). Electron paramagnetic resonance spectroscopy also demonstrated a physical interaction between spin-labeled Aβ and the TR extracellular domain in solution. Furthermore, TR also interacted with AβPP and enhanced its cleavage by α-secretase. Both cellular expression of TR and application of recombinant TR extracellular domain protected N2a neurons from AβO-induced neuronal death. These data provide first evidence that neuronal and astrocytic expression of TR is intimately related to Aβ metabolism and toxicity, and could be neuroprotective through its direct interaction with Aβ and AβPP.
    Full-text Article · Sep 2015 · Journal of Alzheimer's disease: JAD
  • [Show abstract] [Hide abstract] ABSTRACT: Alzheimer's disease is characterized by the presence of extracellular plaques comprised of amyloid beta (Aβ) peptides. Soluble oligomers of the Aβ peptide underlie a cascade of neuronal loss and dysfunction associated with Alzheimer's disease. Single particle analyses of Aβ oligomers in solution by fluorescence correlation spectroscopy (FCS) were used to provide real-time descriptions of how spin-labeled fluorenes (SLFs; bi-functional small molecules that block the toxicity of Aβ) prevent and disrupt oligomeric assemblies of Aβ in solution. Furthermore, the circular dichroism (CD) spectrum of untreated Aβ shows a continuous, progressive change over a 24-hour period, while the spectrum of Aβ treated with SLF remains relatively constant following initial incubation. These findings suggest the conformation of Aβ within the oligomer provides a complementary determinant of Aβ toxicity in addition to oligomer growth and size. Although SLF does not produce a dominant state of secondary structure in Aβ, it does induce a net reduction in beta secondary content compared to untreated samples of Aβ. The FCS results, combined with electron paramagnetic resonance spectroscopy and CD spectroscopy, demonstrate SLFs can inhibit the growth of Aβ oligomers and disrupt existing oligomers, while retaining Aβ as a population of smaller, yet largely disordered oligomers.
    Article · Sep 2015 · Biochimica et Biophysica Acta (BBA) - Proteins & Proteomics
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    Liang Zhang · Song Zhang · Izumi Maezawa · [...] · Eugenia Trushina
    [Show abstract] [Hide abstract] ABSTRACT: Development of therapeutic strategies to prevent Alzheimer's disease (AD) is of great importance. We show that mild inhibition of mitochondrial complex I with small molecule CP2 reduces levels of amyloid beta and phospho-Tau and averts cognitive decline in three animal models of familial AD. Low-mass molecular dynamics simulations and biochemical studies confirmed that CP2 competes with flavin mononucleotide for binding to the redox center of complex I leading to elevated AMP/ATP ratio and activation of AMP-activated protein kinase in neurons and mouse brain without inducing oxidative damage or inflammation. Furthermore, modulation of complex I activity augmented mitochondrial bioenergetics increasing coupling efficiency of respiratory chain and neuronal resistance to stress. Concomitant reduction of glycogen synthase kinase 3β activity and restoration of axonal trafficking resulted in elevated levels of neurotrophic factors and synaptic proteins in adult AD mice. Our results suggest that metabolic reprogramming induced by modulation of mitochondrial complex I activity represents promising therapeutic strategy for AD.
    Full-text Article · Mar 2015 · EBioMedicine
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    Lee-Way Jin · Makoto Horiuchi · Heike Wulff · [...] · Izumi Maezawa
    [Show abstract] [Hide abstract] ABSTRACT: Rett syndrome (RTT) is an autism spectrum disorder caused by loss-of-function mutations in the gene encoding MeCP2, an epigenetic modulator that binds the methyl CpG dinucleotide in target genes to regulate transcription. Previously, we and others reported a role of microglia in the pathophysiology of RTT. To understand the mechanism of microglia dysfunction in RTT, we identified a MeCP2 target gene, SLC38A1, which encodes a major glutamine transporter (SNAT1), and characterized its role in microglia. We found that MeCP2 acts as a microglia-specific transcriptional repressor of SNAT1. Because glutamine is mainly metabolized in the mitochondria, where it is used as an energy substrate and a precursor for glutamate production, we hypothesize that SNAT1 overexpression in MeCP2-deficient microglia would impair the glutamine homeostasis, resulting in mitochondrial dysfunction as well as microglial neurotoxicity because of glutamate overproduction. Supporting this hypothesis, we found that MeCP2 downregulation or SNAT1 overexpression in microglia resulted in (1) glutamine-dependent decrease in microglial viability, which was corroborated by reduced microglia counts in the brains of MECP2 knock-out mice; (2) proliferation of mitochondria and enhanced mitochondrial production of reactive oxygen species; (3) increased oxygen consumption but decreased ATP production (an energy-wasting state); and (4) overproduction of glutamate that caused NMDA receptor-dependent neurotoxicity. The abnormalities could be rectified by mitochondria-targeted expression of catalase and a mitochondria-targeted peptide antioxidant, Szeto-Schiller 31. Our results reveal a novel mechanism via which MeCP2 regulates bioenergetic pathways in microglia and suggest a therapeutic potential of mitochondria-targeted antioxidants for RTT. Copyright © 2015 the authors 0270-6474/15/352516-14$15.00/0.
    Full-text Article · Feb 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
  • Article · Jan 2015 · Biophysical Journal
  • [Show abstract] [Hide abstract] ABSTRACT: Various condensation and ring-closing reactions were used for the syntheses of 3-[(alkylamino)methylene]-6-methylpyri-dine-2,4(1H,3H)-diones, bicyclic pyridinones, and tricyclic morpholinopyrones. For instance, 3-[(dialkylamino)methylene]-6-methylpyridine-2,4(1H,3H)-diones were synthesized from the condensation of dialkylamines and 3-formyl-4-hydroxy-6-methylpyridin-2(1H)-one. 3-Formyl-4-hydroxy-6-methylpyridin-2(1H)-one, derived from 3-formyl-4-hydroxy-6-methylpyridin-2(1H)-one, was used to construct a number of bicyclic pyridinones via a one-pot Knoevenagal and intramolecular lactonization reaction. Tricyclic morpholinopyrones were assembled from a dialkylation reaction involving a dinucleophile, 3-amino-4-hydroxy-6-methyl-2H-pyran-2-one, and a dielectrophile, trans-3,6-dibromocyclohexene. Depending on the reaction conditions, isomers of the tricyclic molecules can be selectively produced, and their chemical structures were unequivocally determined using single-crystal X-ray analyses and 2D COSY spectroscopy. The fluorescently active bicyclic pyridinone compounds show longer absorption (368-430 nm; maximum) and emission wavelengths (450-467 nm) than those of 7-amino-4-methylcoumarin (AMC; λabs,max = 350 nm; λem = 430 nm) suggesting these molecules, such as 3-(2-aminoacetyl)-7-methyl-2H-pyrano[3,2-c]pyridine-2,5(6H)-dione, can be employed as fluorescence activity based probes for tracing biological pathways.
    Article · Aug 2014 · Synthesis
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    Full-text Article · Jul 2014
  • Akira Monji · Izumi Maezawa · Yoshito Mizoguchi · [...] · L.-W. Jin
    [Show abstract] [Hide abstract] ABSTRACT: The etiology of neuropsychiatric disorders such as autism spectrum disorders (ASDs) and schizophrenia remains unclear. However, many aspects of their neuropathology were recently reported to be closely associated with microglial dysfunction. Microglia, which are the major players of innate immunity in the central nervous system, respond rapidly to pathological changes, even minor ones, and contribute directly to neuroinflammation by producing various cytokines and free radicals. Recent studies revealed that microglia become activated over the course of ASDs and schizophrenia, using brain neuroimaging and postmortem analyzes. Recent studies have also shown inhibitory effects of some antipsychotics on the release of inflammatory cytokines and free radicals from activated microglia, causing synaptic and white matter abnormalities as seen in ASDs and schizophrenia postmortem brains. In addition, recent evidence strongly suggests a neurodevelopmental role for microglia in regulating the formation/function of neuronal circuits by their phagocytic activity and structural interactions with synapses. In Rett syndrome (RTT) particularly, microglia become dysfunctional and neurotoxic, thus contributing to abnormal brain development. Populating the brain of RTT mice with wild-type microglia was also found to arrest the disease, indicating an essential role of microglia in regulating the neurodevelopmental trajectory. In summary, emerging evidence indicates that microglia are closely related to the progression and outcome of ASDs and schizophrenia. Understanding microglial pathology may shed new light on the most promising therapeutic strategies for ASDs and schizophrenia, among other neuropsychiatric disorders. © 2014 Springer Science+Business Media New York. All rights reserved.
    Article · Jul 2014
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    Jianyu Lu · Izumi Maezawa · Sahani Weerasekara · [...] · Duy H Hua
    [Show abstract] [Hide abstract] ABSTRACT: A new series of fifteen 5-, 6-, and 8-appended 4-methylquinolines were synthesized and evaluated for their neural protective activities. Selected compounds were further examined for their inhibition of glycogen synthase kinase-3β (GSK-3β) and protein kinase C (PKC). Two most potent analogs, compounds 3 and 10, show nanomolar protective activities in amyloid β-induced MC65 cells and enzymatic inhibitory activities against GSK-3β, but poor PKC inhibitory activities. Using normal mouse model, the distribution of the most potent analog 3 in various tissues and possible toxic effects in the locomotors and inhibition of liver transaminases activities were carried out. No apparent decline of locomotor activity and no inhibition of liver transaminases were found. The compound appears to be safe for long-term use in Alzheimer's disease mouse model.
    Full-text Article · Jun 2014 · Bioorganic & Medicinal Chemistry Letters
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    Tamás Kálai · Robin Altman · Izumi Maezawa · [...] · Kálmán Hideg
    [Show abstract] [Hide abstract] ABSTRACT: A series of new Tacrine analogs modified with nitroxides or pre-nitroxides on 9-amino group via methylene or piperazine spacers were synthesized; the nitroxide or its precursors were incorporated into the Tacrine scaffold. The new compounds were tested for their hydroxyl radical and peroxyl radical scavenging ability, acetylcholinesterase inhibitor activity and protection against Aβ-induced cytotoxicity. Based on these assays, we conclude that Tacrine analogs connected to five and six-membered nitroxides via piperazine spacers (9b, 9b/HCl and 12) exhibited the best activity, providing direction for further development of additional candidates with dual functionality (anti Alzheimer's and antioxidant).
    Full-text Article · Apr 2014 · European Journal of Medicinal Chemistry
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    Dag H Yasui · Huichun Xu · Keith W Dunaway · [...] · Izumi Maezawa
    [Show abstract] [Hide abstract] ABSTRACT: Primers used for RT-PCR. Table S2. RNA transcripts altered by loss of MeCP2 (P < 0.0005). Table S3. Primers used for ChIP-seq validation.
    Full-text Dataset · Jan 2013
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    Dag H Yasui · Huichun Xu · Keith W Dunaway · [...] · Izumi Maezawa
    [Show abstract] [Hide abstract] ABSTRACT: Background Mutations in MECP2 encoding methyl-CpG-binding protein 2 (MeCP2) cause the X-linked neurodevelopmental disorder Rett syndrome. Rett syndrome patients exhibit neurological symptoms that include irregular breathing, impaired mobility, stereotypic hand movements, and loss of speech. MeCP2 protein epigenetically modulates gene expression through genome-wide binding to methylated CpG dinucleotides. While neurons have the highest level of MeCP2 expression, astrocytes and other cell types also express detectable levels of MeCP2. Recent studies suggest that astrocytes likely control the progression of Rett syndrome. Thus, the object of these studies was to identify gene targets that are affected by loss of MeCP2 binding in astrocytes. Methods To identify gene targets of MeCP2 in astrocytes, combined approaches of expression microarray and chromatin immunoprecipitation of MeCP2 followed by sequencing (ChIP-seq) were compared between wild-type and MeCP2-deficient astrocytes. MeCP2 gene targets were compared with genes in the top 10% of MeCP2 binding levels in gene windows either within 2 kb upstream of the transcription start site, or the ‘gene body’ that extended from transcription start to end site, or 2 kb downstream of the transcription end site. Results A total of 118 gene transcripts surpassed the highly significant threshold (P < 0.005, fold change > 1.2) in expression microarray analysis from triplicate cultures. The top 10% of genes with the highest levels of MeCP2 binding were identified in two independent ChIP-seq experiments. Together this integrated, genome-wide screen for MeCP2 target genes provided an overlapping list of 19 high-confidence MeCP2-responsive gene transcripts in astrocytes. Validation of candidate target gene transcripts by RT-PCR revealed that expression of Apoc2, Cdon, Csrp and Nrep were consistently responsive to MeCP2 deficiency in astrocytes. Conclusions The first MeCP2 ChIP-seq and gene expression microarray analysis in astrocytes reveals a set of potential MeCP2 target genes that may contribute to normal astrocyte signaling, cell division and neuronal support functions, the loss of which may contribute to the Rett syndrome phenotype.
    Full-text Article · Jan 2013 · Molecular Autism
  • Laxman Pokhrel · Izumi Maezawa · Thi D T Nguyen · [...] · Duy H Hua
    [Show abstract] [Hide abstract] ABSTRACT: A major effort in Alzheimer's disease therapeutic development has targeted Aβ and downstream events. We have synthesized a small library of tricyclic pyrone compounds. Their protective action in MC65 cells and inhibition of ACAT along with the upregulation of cholesterol transporter gene were investigated. Five active compounds exhibited potencies in the nanomolar ranges. The multiple effects of the compounds on Aβ and cellular cholesterol pathways could be potential mechanisms underlying the protective effects in vivo.
    Article · Oct 2012 · Journal of Medicinal Chemistry
  • Article · Jul 2012 · Alzheimer's and Dementia
  • Izumi Maezawa · Paul David Jenkins · Jessica Sexton · [...] · Lee-Way Jin
    Article · Jul 2012 · Alzheimer's and Dementia
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    [Show abstract] [Hide abstract] ABSTRACT: There exists an urgent need for new target discovery to treat Alzheimer's disease (AD); however, recent clinical trials based on anti-Aβ and anti-inflammatory strategies have yielded disappointing results. To expedite new drug discovery, we propose reposition targets which have been previously pursued by both industry and academia for indications other than AD. One such target is the calcium-activated potassium channel KCa3.1 (KCNN4), which in the brain is primarily expressed in microglia and is significantly upregulated when microglia are activated. We here review the existing evidence supporting that KCa3.1 inhibition could block microglial neurotoxicity without affecting their neuroprotective phagocytosis activity and without being broadly immunosuppressive. The anti-inflammatory and neuroprotective effects of KCa3.1 blockade would be suitable for treating AD as well as cerebrovascular and traumatic brain injuries, two well-known risk factors contributing to the dementia in AD patients presenting with mixed pathologies. Importantly, the pharmacokinetics and pharmacodynamics of several KCa3.1 blockers are well known, and a KCa3.1 blocker has been proven safe in clinical trials. It is therefore promising to reposition old or new KCa3.1 blockers for AD preclinical and clinical trials.
    Full-text Article · May 2012 · International Journal of Alzheimer's Disease