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1.
Am J Hum Genet ; 104(5): 925-935, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982609

RESUMO

Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease. We identified five CSF1R mutations that were homozygous or compound heterozygous in these affected individuals. Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA. Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic. Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function.

2.
Arch Biochem Biophys ; 663: 120-128, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30629958

RESUMO

BACKGROUND: Vitamin C (l-ascorbic acid, VC) and vitamin E (α-tocopherol, VE) play important physiological roles as endogenous antioxidants in many tissues and organs. However, their roles in the brain remain entirely elusive. We established senescence marker protein 30 (SMP30)/α-tocopherol transfer protein (αTTP) double knockout (DKO) mice as a novel VC and VE double-deficiency model and examined the effect of VC and VE double-deficiency on brain functions. METHODS: DKO and wild-type (WT) mice were divided into the following two groups: mice in the CE (+) group were supplied with sufficient amounts of VC and VE and mice in the CE (-) group were deficient in both VC and VE. After 8 weeks of CE (+) or CE (-) treatments, a battery of behavioral experiments was conducted to analyze cognitive functions, including memory, through the Morris water maze and Pavlovian fear conditioning tasks. RESULTS: The plasma VC and VE levels in DKO-CE (-) mice and VE level in WT-CE (-) mice were almost completely depleted after 8 weeks of the deficient treatment. The behavioral study revealed that the general behaviors, including locomotor activity and anxiety level, were not influenced by the CE (-) treatment in DKO and WT mice. However, in the Pavlovian fear conditioning task, DKO-CE (-) mice showed impaired conditioned fear memory compared with that of DKO-CE (+) mice. Furthermore, increased mRNA expression was observed in inflammatory-related genes, such as IL-6, TNFα, F4/80, and Mcp-1, in the hippocampus of DKO-CE (-) mice. CONCLUSIONS: The findings of this study provide evidence that VC and VE deficiency led to impaired conditioned fear memory possibly caused by neuroinflammation in the brain.

3.
Intern Med ; 58(7): 1003-1006, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30568118

RESUMO

Cerebellar damage can cause not only disturbance in motor control but also higher brain dysfunction known as cerebellar cognitive affective syndrome (CCAS). Although CCAS has a high prevalence, the precise mechanism and effective medications are unknown. We herein report a CCAS patient whose symptoms were ameliorated with the cholinesterase inhibitor donepezil. N-isopropyl-p-123I-iodoamphetamine-single-photon emission computed tomography showed improvement in hypoperfusion in the contralateral frontal and parieto-temporal lobes. Some projections with cholinergic transmission might form a functional connectivity between the cerebellum and contralateral association cortices, and cholinergic dysfunction is involved in CCAS pathophysiology. Donepezil might be worth considering for some CCAS patients.


Assuntos
Doenças Cerebelares/tratamento farmacológico , Cerebelo/diagnóstico por imagem , Circulação Cerebrovascular/fisiologia , Cognição/fisiologia , Donepezila/uso terapêutico , Doenças Cerebelares/diagnóstico , Doenças Cerebelares/fisiopatologia , Cerebelo/irrigação sanguínea , Inibidores da Colinesterase/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada de Emissão de Fóton Único
5.
Lancet Neurol ; 17(6): 519-529, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29685815

RESUMO

BACKGROUND: Despite the introduction of plasmapheresis and immunoglobulin therapy, many patients with Guillain-Barré syndrome still have an incomplete recovery. Evidence from pathogenesis studies suggests the involvement of complement-mediated peripheral nerve damage. We aimed to investigate the safety and efficacy of eculizumab, a humanised monoclonal antibody against the complement protein C5, in patients with severe Guillain-Barré syndrome. METHODS: This study was a 24 week, multicentre, double-blind, placebo-controlled, randomised phase 2 trial done at 13 hospitals in Japan. Eligible patients with Guillain-Barré syndrome were aged 18 years or older and could not walk independently (Guillain-Barré syndrome functional grade 3-5). Patients were randomly assigned (2:1) to receive 4 weeks of intravenous immunoglobulin plus either eculizumab (900 mg) or placebo; randomisation was done via a computer-generated process and web response system with minimisation for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade ≤2] at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy endpoint, we predefined a response rate threshold of the lower 90% CI boundary exceeding 50%. This trial is registered with ClinicalTrials.gov, number, NCT02493725. FINDINGS: Between Aug 10, 2015, and April 21, 2016, 34 patients were assigned to receive either eculizumab (n=23) or placebo (n=11). At week 4, the proportion of the patients able to walk independently (functional grade ≤2) was 61% (90% CI 42-78; n=14) in the eculizumab group, and 45% (20-73; n=5) in the placebo group. Adverse events occurred in all 34 patients. Three patients had serious adverse events: two in the eculizumab group (anaphylaxis in one patient and intracranial haemorrhage and abscess in another patient) and one in the placebo group (depression). The possibility that anaphylaxis and intracranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred. INTERPRETATION: The primary outcome measure did not reach the predefined response rate. However, because this is a small study without statistical comparison with the placebo group, the efficacy and safety of eculizumab could be investigated in larger, randomised controlled trials. FUNDING: The Japan Agency for Medical Research and Development, Ministry of Health, Labor and Welfare, and Alexion Pharmaceuticals.

6.
JMIR Res Protoc ; 5(4): e210, 2016 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-27821382

RESUMO

BACKGROUND: Guillain-Barré syndrome (GBS) is an immune-mediated neuropathy that causes acute flaccid paralysis. Immunoglobulin and plasma exchange are established treatments for GBS; however, a substantial number of patients, particularly those with severe disease, have poor recovery and residual deficits. Recent studies suggest that complement activation plays a pivotal role in GBS-associated axonal degeneration, and eculizumab is a humanized monoclonal antibody that specifically binds to complement component 5 and potently inhibits complement activation. OBJECTIVE: This clinical trial aims to evaluate the efficacy and safety of eculizumab, a humanized monoclonal antibody directed against complement component 5, for treatment of GBS. METHODS: The Japanese Eculizumab Trial for GBS (JET-GBS) is a prospective, multicenter, placebo-controlled, double-blind, randomized phase II study conducted at 13 tertiary neurology centers and is funded by the Japan Agency for Medical Research and Development. A total of 33 GBS patients unable to walk independently within 2 weeks from symptom onset (Hughes functional grade 3-5) were randomized at a 2:1 ratio to receive either intravenous eculizumab (900 mg/day) or placebo once weekly for 4 weeks, followed by 20 weeks of follow-up. The primary endpoint for efficacy is the proportion of patients who regain their ability to walk without aid at 4 weeks after the first dose of the study treatment, while primary safety outcomes are the incidence of adverse events and serious adverse events during the trial. RESULTS: Enrollment for the trial began in August 2015. This trial is still ongoing. All participants have been enrolled, and follow-up will be completed in October 2016. CONCLUSIONS: This study is the first to investigate the efficacy and safety of eculizumab for GBS. In case of a positive result, we will plan a phase III trial to investigate this issue in a larger number of patients. CLINICALTRIAL: UMIN Clinical Trials Registry UMIN 000018171; https:/upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function= brows&action=brows&type=summary&language=J&recptno=R000020978 (Archived by WebCite at http://www.webcitation.org/ 6lTiG8ltG). Clinical Trials.gov NCT02493725; https://clinicaltrials.gov/ct2/show/NCT02493725 (Archived by WebCite at http://www.webcitation.org/6lVJZXKSL).

7.
PLoS One ; 10(12): e0143518, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26637123

RESUMO

Oxidative stress has a ubiquitous role in neurodegenerative diseases and oxidative damage in specific regions of the brain is associated with selective neurodegeneration. We previously reported that Alzheimer disease (AD) model mice showed decreased insulin-degrading enzyme (IDE) levels in the cerebrum and accelerated phenotypic features of AD when crossbred with alpha-tocopherol transfer protein knockout (Ttpa-/-) mice. To further investigate the role of chronic oxidative stress in AD pathophysiology, we performed DNA microarray analysis using young and aged wild-type mice and aged Ttpa-/- mice. Among the genes whose expression changed dramatically was Phospholipase A2 group 3 (Pla2g3); Pla2g3 was identified because of its expression profile of cerebral specific up-regulation by chronic oxidative stress in silico and in aged Ttpa-/- mice. Immunohistochemical studies also demonstrated that human astrocytic Pla2g3 expression was significantly increased in human AD brains compared with control brains. Moreover, transfection of HEK293 cells with human Pla2g3 decreased endogenous IDE expression in a dose-dependent manner. Our findings show a key role of Pla2g3 on the reduction of IDE, and suggest that cerebrum specific increase of Pla2g3 is involved in the initiation and/or progression of AD.


Assuntos
Envelhecimento/genética , Doença de Alzheimer/genética , Cérebro/metabolismo , Fosfolipases A2 do Grupo III/genética , Insulisina/genética , Doença de Alzheimer/metabolismo , Animais , Proteínas de Transporte/genética , Células Cultivadas , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Técnicas de Inativação de Genes , Fosfolipases A2 do Grupo III/metabolismo , Células HEK293 , Humanos , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Especificidade de Órgãos , Estresse Oxidativo , Regulação para Cima
8.
Nat Neurosci ; 18(4): 521-530, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25730668

RESUMO

The glucose transporter GLUT1 at the blood-brain barrier (BBB) mediates glucose transport into the brain. Alzheimer's disease is characterized by early reductions in glucose transport associated with diminished GLUT1 expression at the BBB. Whether GLUT1 reduction influences disease pathogenesis remains, however, elusive. Here we show that GLUT1 deficiency in mice overexpressing amyloid ß-peptide (Aß) precursor protein leads to early cerebral microvascular degeneration, blood flow reductions and dysregulation and BBB breakdown, and to accelerated amyloid ß-peptide (Aß) pathology, reduced Aß clearance, diminished neuronal activity, behavioral deficits, and progressive neuronal loss and neurodegeneration that develop after initial cerebrovascular degenerative changes. We also show that GLUT1 deficiency in endothelium, but not in astrocytes, initiates the vascular phenotype as shown by BBB breakdown. Thus, reduced BBB GLUT1 expression worsens Alzheimer's disease cerebrovascular degeneration, neuropathology and cognitive function, suggesting that GLUT1 may represent a therapeutic target for Alzheimer's disease vasculo-neuronal dysfunction and degeneration.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica , Circulação Cerebrovascular/fisiologia , Endotélio Vascular , Transportador de Glucose Tipo 1/deficiência , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/fisiopatologia , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
10.
J Neurol Sci ; 345(1-2): 228-30, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25066259

RESUMO

Ataxia with isolated vitamin E deficiency (AVED) is a neurodegenerative disease caused by a mutation in the α-tocopherol transfer protein gene (TTPA). The clinical features of the disease resemble Friedreich's ataxia. However, AVED is associated with low plasma vitamin E levels, which results in compromised antioxidant function. Dysregulation of this lipid-soluble antioxidant vitamin plays a major role in the neurodegeneration observed in AVED. Some AVED patients experience decreased visual acuity. Retinitis pigmentosa is thought to be the main cause of this visual impairment. Although antioxidant levels are important for the prevention of macular degeneration, there have been no reports of macular degeneration in AVED. Here, we describe a patient with AVED with progressive macular degeneration, who carried a novel truncating mutation-c.717 del C (p.D239EfsX25)-in exon 5 of the TTPA gene. These findings suggest that this newly identified mutation results in severely low serum vitamin E levels, which may be associated with the development of retinitis pigmentosa and macular degeneration.


Assuntos
Ataxia/complicações , Ataxia/genética , Proteínas de Transporte/genética , Deleção de Genes , Degeneração Macular/etiologia , Retinite Pigmentosa/etiologia , Deficiência de Vitamina E/complicações , Deficiência de Vitamina E/genética , Feminino , Humanos , Pessoa de Meia-Idade
12.
Chem Pharm Bull (Tokyo) ; 61(5): 592-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23649203

RESUMO

Five new norlanostane-type triterpenoid glycosides were isolated from the bulbs of Scilla scilloides DRUCE (Liliaceae). Their chemical structures were determined on the basis of spectroscopic data as well as chemical evidence.


Assuntos
Glicosídeos/isolamento & purificação , Raízes de Plantas/química , Scilla/química , Triterpenos/isolamento & purificação , Glicosídeos/química , Estrutura Molecular , Estereoisomerismo , Triterpenos/química
13.
J Biol Chem ; 288(21): 15154-66, 2013 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-23580652

RESUMO

Soluble low density lipoprotein receptor-related protein-1 (sLRP1) binds ~70% of amyloid ß-peptide (Aß) in human plasma. In Alzheimer disease (AD) and individuals with mild cognitive impairment converting to AD, plasma sLRP1 levels are reduced and sLRP1 is oxidized, which results in diminished Aß peripheral binding and higher levels of free Aß in plasma. Experimental studies have shown that free circulating Aß re-enters the brain and that sLRP1 and/or its recombinant wild type cluster IV (WT-LRPIV) prevent Aß from entering the brain. Treatment of Alzheimer APPsw(+/0) mice with WT-LRPIV has been shown to reduce brain Aß pathology. In addition to Aß, LRPIV binds multiple ligands. To enhance LRPIV binding for Aß relative to other LRP1 ligands, we generated a library of LRPIV-derived fragments and full-length LRPIV variants with glycine replacing aspartic acid residues 3394, 3556, and 3674 in the calcium binding sites. Compared with WT-LRPIV, a lead LRPIV-D3674G mutant had 1.6- and 2.7-fold higher binding affinity for Aß40 and Aß42 in vitro, respectively, and a lower binding affinity for other LRP1 ligands (e.g. apolipoprotein E2, E3, and E4 (1.3-1.8-fold), tissue plasminogen activator (2.7-fold), matrix metalloproteinase-9 (4.1-fold), and Factor Xa (3.8-fold)). LRPIV-D3674G cleared mouse endogenous brain Aß40 and Aß42 25-27% better than WT-LRPIV. A 3-month subcutaneous treatment of APPsw(+/0) mice with LRPIV-D3674G (40 µg/kg/day) reduced Aß40 and Αß42 levels in the hippocampus, cortex, and cerebrospinal fluid by 60-80% and improved cerebral blood flow responses and hippocampal function at 9 months of age. Thus, LRPIV-D3674G is an efficient new Aß clearance therapy.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Fragmentos de Peptídeos/metabolismo , Receptores de LDL/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Substituição de Aminoácidos , Peptídeos beta-Amiloides/genética , Animais , Células CHO , Córtex Cerebral/patologia , Circulação Cerebrovascular/genética , Cricetinae , Cricetulus , Hipocampo/patologia , Humanos , Ligantes , Camundongos , Camundongos Mutantes , Mutação de Sentido Incorreto , Fragmentos de Peptídeos/genética , Ligação Proteica/genética , Receptores de LDL/genética , Proteínas Supressoras de Tumor/genética
15.
Brain Nerve ; 65(2): 145-51, 2013 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-23399672

RESUMO

Alzheimer's disease (AD) is the most common cause of dementia, and its pathological hallmarks are senile plaques and neurofibrillary tangles in the brain, which eventually induce neuronal death. The prevailing hypothesis for the pathomechanism of AD is the amyloid cascade hypthesis: amyloid-ß peptide (Aß) deposition in the brain initiates a sequence of events leading to dementia. The blood-brain barrier (BBB) is crucial for AD pathomechanism because the transport of Aß across the BBB is regulated by the receptor for advanced glycation end products, low-density lipoprotein receptor-related proteins, and the P-glycoprotein. Many studies have elucidated that these transport proteins are impaired in AD patients. Moreover, it is now widely recognized that most cases of AD show vascular pathology. Vascular risk factors such as diabetes mellitus, hypertension, hypercholesterolemia, and obesity are risk factors for AD. Recently, the vascular hypothesis for AD pathomechanism has been proposed; vascular risk factors first lead to BBB dysfunction and oligaemia and then induce Aß deposition, toxic accumulates, and capillary hypoperfusion in the brain, ultimately leading to neuronal dysfunction. Therapeutic strategies for Aß clearance from the brain to blood across the BBB have been increasingly developed. The "peripheral sink" approaches are now challenged by anti-Aß antibodies, the agents with high affinity to Aß, and the modification of molecules that influence the Aß transport across the BBB. This review highlights the roles of the BBB in AD pathomechanism and its importance in designing therapeutic strategies.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Barreira Hematoencefálica/metabolismo , Amiloide/metabolismo , Animais , Anticorpos/uso terapêutico , Transporte Biológico/fisiologia , Barreira Hematoencefálica/patologia , Humanos
16.
Chem Pharm Bull (Tokyo) ; 60(10): 1314-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23036971

RESUMO

Two new norlanostane-type triterpenoid glycosides and a new phenylpropanoid glycoside were isolated from the bulbs of Scilla scilloides DRUCE (Liliaceae), along with two known alkaloids. Their chemical structures were determined on the basis of spectroscopic data as well as chemical evidence.


Assuntos
Glicosídeos/química , Scilla/química , Sequência de Carboidratos , Glicosídeos/isolamento & purificação , Espectroscopia de Ressonância Magnética , Dados de Sequência Molecular , Fenóis/química , Fenóis/isolamento & purificação , Raízes de Plantas/química , Triterpenos/química , Triterpenos/isolamento & purificação
18.
Chem Pharm Bull (Tokyo) ; 59(11): 1348-54, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22041070

RESUMO

Three new norlanostane-type triterpene glycosides, scillanostasides A, B, and C, and two new lanostane-type triterpene glycosides, scillanostasides D and E, were isolated from the bulbs of Scilla scilloides Druce (Liliaceae) along with one known norlanostane-type triterpene heptaglycoside, scillascilloside G-1. Their chemical structures were determined on the basis of spectroscopic data as well as chemical evidence.


Assuntos
Glicosídeos/química , Scilla/química , Triterpenos/química , Glicosídeos/isolamento & purificação , Espectroscopia de Ressonância Magnética , Conformação Molecular , Raízes de Plantas/química
20.
J Biol Chem ; 284(48): 33400-8, 2009 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-19679659

RESUMO

Increased oxidative damage is a prominent and early feature in Alzheimer disease. We previously crossed Alzheimer disease transgenic (APPsw) model mice with alpha-tocopherol transfer protein knock-out (Ttpa(-/-)) mice in which lipid peroxidation in the brain was significantly increased. The resulting double-mutant (Ttpa(-/-)APPsw) mice showed increased amyloid beta (Abeta) deposits in the brain, which was ameliorated with alpha-tocopherol supplementation. To investigate the mechanism of the increased Abeta accumulation, we here studied generation, degradation, aggregation, and efflux of Abeta in the mice. The clearance of intracerebral-microinjected (125)I-Abeta(1-40) from brain was decreased in Ttpa(-/-) mice to be compared with wild-type mice, whereas the generation of Abeta was not increased in Ttpa(-/-)APPsw mice. The activity of an Abeta-degrading enzyme, neprilysin, did not decrease, but the expression level of insulin-degrading enzyme was markedly decreased in Ttpa(-/-) mouse brain. In contrast, Abeta aggregation was accelerated in Ttpa(-/-) mouse brains compared with wild-type brains, and well known molecules involved in Abeta transport from brain to blood, low density lipoprotein receptor-related protein-1 (LRP-1) and p-glycoprotein, were up-regulated in the small vascular fraction of Ttpa(-/-) mouse brains. Moreover, the disappearance of intravenously administered (125)I-Abeta(1-40) was decreased in Ttpa(-/-) mice with reduced translocation of LRP-1 in the hepatocytes. These results suggest that lipid peroxidation due to depletion of alpha-tocopherol impairs Abeta clearances from the brain and from the blood, possibly causing increased Abeta accumulation in Ttpa(-/-)APPsw mouse brain and plasma.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Proteínas de Transporte/metabolismo , Tocoferóis/metabolismo , Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/farmacocinética , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Northern Blotting , Western Blotting , Encéfalo/efeitos dos fármacos , Proteínas de Transporte/genética , Suplementos Nutricionais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , alfa-Tocoferol/administração & dosagem , alfa-Tocoferol/farmacologia
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