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1.
J Alzheimers Dis ; 91(3): 1173-1183, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36565118

RESUMO

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers in patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) have demonstrated inconsistent results. OBJECTIVE: We investigated the relationship between CSF amyloid-ß protein (Aß) and vascular pathological findings to elucidate the mechanisms of Aß elimination from the brain in CAA-ri. METHODS: We examined Aß40 and Aß42 levels in CSF samples in 15 patients with CAA-ri and 15 patients with Alzheimer's disease and cerebral amyloid angiopathy (AD-CAA) using ELISA as a cross-sectional study. Furthermore, we pathologically examined Aß40 and Aß42 depositions on the leptomeningeal blood vessels (arteries, arterioles, and veins) using brain biopsy samples from six patients with acute CAA-ri and brain tissues of two autopsied patients with CAA-ri. RESULTS: The median Aß40 and Aß42 levels in the CSF showed no significant difference between pre-treatment CAA-ri (Aß40, 6837 pg/ml; Aß42, 324 pg/ml) and AD-CAA (Aß40, 7669 pg/ml, p = 0.345; Aß42, 355 pg/ml, p = 0.760). Aß40 and Aß42 levels in patients with post-treatment CAA-ri (Aß40, 1770 pg/ml, p = 0.056; Aß42, 167 pg/ml, p = 0.006) were lower than those in patients with pre-treatment CAA-ri. Regarding Aß40 and Aß42 positive arteries, acute CAA-ri cases showed a higher frequency of partially Aß-deposited blood vessels than postmortem CAA-ri cases (Aß40, 20.8% versus 3.9%, p = 0.0714; Aß42, 27.4% versus 2.0%, p = 0.0714, respectively). CONCLUSION: Lower levels of CSF Aß40 and Aß42 could be biomarkers for the cessation of inflammation in CAA-ri reflecting the recovery of the intramural periarterial drainage pathway and vascular function.


Assuntos
Doença de Alzheimer , Angiopatia Amiloide Cerebral , Humanos , Estudos Transversais , Angiopatia Amiloide Cerebral/patologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/patologia , Doença de Alzheimer/patologia , Inflamação/metabolismo , Biomarcadores/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano
4.
Acta Neurol Scand ; 143(4): 450-457, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33247941

RESUMO

OBJECTIVES: To clarify pathomechanisms of cerebral amyloid angiopathy-related inflammation/vasculitis (CAA-ri). METHODS: We collected cerebrospinal fluid (CSF) samples of nine patients with CAA-ri of before (acute CAA-ri group) and after treatment (post-treatment CAA-ri group) and nine patients with CAA (CAA without inflammation group). We examined anti-amyloid ß protein (Aß) antibody titer by ELISA, and measured 27 Cytokines, nine matrix metalloproteinases (MMPs), and four tissue inhibitors of MMPs (TIMPs) by multiplexed fluorescent bead-based immunoassay. RESULTS: We demonstrated TIMP-2 (median) in CSF of the acute CAA-ri group (30,994.49 pg/ml, p = 0.007) and the post-treatment CAA-ri group (36,430.97 pg/ml, p = 0.001) was significantly elevated compared to that of the CAA without inflammation group (22,013.58 pg/ml). TIMP-1 was also higher in the post-treatment CAA-ri group than that in the CAA without inflammation group (58,167.75 pg/ml vs. 45,770.03 pg/ml, p = 0.005). There was a significant positive correlation between TIMP-1 and anti-Aß antibodies in CAA-ri (rs  = 0.900, p = 0.037). Median MMP-2 tended to be higher in the acute and post-treatment CAA-ri groups (10,619.82 pg/ml and 8396.98 pg/ml, respectively) than in the CAA without inflammation group (4436.34 pg/ml). Platelet-derived growth factor (PDGF)-BB levels before treatment were higher than those after treatment (median, 12.66 pg/ml vs. 6.39 pg/ml; p = 0.011) and correlated with the titer of anti-Aß antibodies (rs  =0.900, p = 0.037). CONCLUSIONS: Elevated levels of MMP-2, TIMP-1, and TIMP-2 might be related to the development of CAA-ri. Elevation of PDGF-BB could be a useful marker for clinical diagnosis of CAA-ri.


Assuntos
Angiopatia Amiloide Cerebral/líquido cefalorraquidiano , Angiopatia Amiloide Cerebral/diagnóstico , Citocinas/líquido cefalorraquidiano , Mediadores da Inflamação/líquido cefalorraquidiano , Metaloproteases/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Estudos Retrospectivos
5.
Neuropathology ; 39(4): 319-323, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31243794

RESUMO

We describe an autopsy-proven case of Parkinson's disease with dementia showing early-onset delusions and hallucinations with limbic-type Lewy body pathology. A Japanese man 72 years old at time of death, developed hand tremor at the age of 45. On neurological examination at 47 years of age, parkinsonian symptoms and signs were present. Pergolide mesylate 1000 µg/day improved his motor symptoms. Then, delusional jealousy appeared and he consulted the psychiatric department in our hospital at the age of 50. Pergolide mesylate 2000 µg/day and trihexyphenidyl hydrochloride 6 mg/day were prescribed. His delusional jealousy made him hit his wife at the age of 63, and visual hallucinations were demonstrated. Brain magnetic resonance imaging (MRI) at the age of 65 revealed mild frontal lobe atrophy. At the age of 72, apparent dementia and dysphagia appeared. The total clinical course was 27 years. The brain showed mild frontal atrophy and weighed 1295 g before fixation. Depigmentation of the substantia nigra and locus ceruleus was macroscopically apparent. Neuronal loss with gliosis was noteworthy in the substantia nigra, locus ceruleus, dorsal vagal nucleus, nucleus basalis of Meynert (NBM), and intermediate lateral nuclei; however, cerebral neocortex and limbic systems were relatively preserved. Widespread occurrence of Lewy bodies with a few Lewy neurites were demonstrated (limbic-type). Noticeable Lewy body pathology in the NBM was shown in contrast to that in other limbic system structures, such as the amygdala and parahippocampal gyrus, and cerebral cortex. In vivo structural imaging studies revealed that cholinergic projections from the NBM could be responsible for generation of cholinergic deficiency syndrome, including delusions and hallucinations. Furthermore, basal forebrain volume is reduced in patients with Parkinson's disease showing visual hallucinations. Prominent Lewy body pathology in the NBM could be related to not only visual hallucinations but also delusions.


Assuntos
Núcleo Basal de Meynert/patologia , Delusões/patologia , Alucinações/patologia , Doença por Corpos de Lewy/patologia , Doença de Parkinson/patologia , Idoso , Encéfalo/patologia , Delusões/complicações , Alucinações/complicações , Humanos , Doença por Corpos de Lewy/complicações , Masculino , Doença de Parkinson/complicações
6.
Mult Scler ; 24(9): 1258-1261, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29676196

RESUMO

The present report discusses the case of a woman with neuromyelitis optica (NMO) who exhibited bilateral optic neuritis, longitudinally extensive myelitis, serum anti-aquaporin-4 antibodies, and a unique pattern of white matter involvement. The disease duration was 26 years, and the patient died at the age of 65 years. Sequential magnetic resonance images obtained during the last 6 years of life revealed leukoencephalopathy-like lesions extending symmetrically and contiguously from the periventricular regions, which had begun to transform into multiple cavities with semi-annular partitions. This unique pattern of white matter abnormalities should thus be considered among those associated with NMO.


Assuntos
Córtex Cerebral/patologia , Leucoencefalopatias/patologia , Neuromielite Óptica/patologia , Substância Branca/patologia , Adulto , Idoso , Córtex Cerebral/diagnóstico por imagem , Feminino , Humanos , Leucoencefalopatias/diagnóstico por imagem , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Necrose/patologia , Neuromielite Óptica/diagnóstico por imagem , Substância Branca/diagnóstico por imagem
8.
J Alzheimers Dis ; 55(3): 905-913, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27802236

RESUMO

BACKGROUND: Alzheimer's disease (AD) commonly accompanies cerebral amyloid angiopathy (CAA). OBJECTIVE: We aimed to reveal associations between CAA-related brain microbleeds and cerebrospinal fluid (CSF) markers in AD patients. METHODS: Patients with probable AD (n = 88) from consecutive patients in our memory clinic were evaluated for patient demographics, vascular risk factors, neuropsychological tests, apolipoprotein E phenotype, MRI including T2*-weighted image and fluid attenuated inversion recovery sequence, and CSF amyloid and tau markers. RESULTS: The 88 patients with AD included 15 with microbleeds only in cortical/subcortical regions (cortical microbleeds) that could be CAA-related, 16 with microbleeds only in deep locations (deep microbleeds), 3 with microbleeds in both cortical and deep locations (mixed microbleeds), and 54 without microbleeds. The CSF levels of amyloid ß-protein 1-40 (Aß40) and amyloid ß-protein 1-42 (Aß42) were significantly lower in patients with cortical microbleeds than in those without microbleeds (p = 0.001 and p = 0.027, respectively). The result remained unchanged after adjustment for age, sex, apolipoprotein E E4 presence, and leukoaraiosis. CONCLUSIONS: CAA-related cortical microbleeds would be associated with lower CSF levels of Aß40 and Aß42 in AD, reflecting the deposition of both Aß40 and Aß42 in the cerebrovasculature.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/complicações , Angiopatia Amiloide Cerebral/líquido cefalorraquidiano , Angiopatia Amiloide Cerebral/complicações , Hemorragias Intracranianas/líquido cefalorraquidiano , Hemorragias Intracranianas/complicações , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/genética , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Angiopatia Amiloide Cerebral/genética , Feminino , Humanos , Hemorragias Intracranianas/diagnóstico por imagem , Leucoaraiose/diagnóstico por imagem , Leucoaraiose/etiologia , Imageamento por Ressonância Magnética , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Estudos Retrospectivos , Fatores de Risco
9.
Spec Care Dentist ; 36(1): 13-7, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26390226

RESUMO

OBJECTIVE: To evaluate the effectiveness of an electric toothbrush for oral care in patients with neuromuscular disability. METHODS: In this randomized observer-blind crossover trial, 30 patients with neuromuscular disease performed either electric or manual toothbrushing each for 4 weeks. Plaque status (plaque control record), periodontal pocket depth, oral status (oral assessment guide), salivary bacterial count, and toothbrushing time were assessed after each period and compared between the two groups by Wilcoxon signed-rank test. RESULTS: Twenty-eight patients completed the study, including 18 communicative patients. Periodontal pockets were significantly shallower and toothbrushing time was significantly shorter with electric toothbrush use than with manual toothbrush use. No significant differences in oral status and salivary bacterial counts were noted between the approaches, but plaque status significantly improved after electric toothbrushing in communicative patients. CONCLUSIONS: Electric toothbrushing is beneficial for maintaining oral health in patients with neuromuscular disability and reducing the caregivers' oral care burden.


Assuntos
Pessoas com Deficiência , Doenças Neuromusculares/fisiopatologia , Escovação Dentária/instrumentação , Estudos Cross-Over , Índice de Placa Dentária , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Índice Periodontal , Saliva/microbiologia , Fatores de Tempo
10.
J Neurochem ; 134(5): 943-55, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26016728

RESUMO

Lewy bodies, mainly composed of α-synuclein (αS), are pathological hallmarks of Parkinson's disease and dementia with Lewy bodies. Epidemiological studies showed that green tea consumption or habitual intake of phenolic compounds reduced Parkinson's disease risk. We previously reported that phenolic compounds inhibited αS fibrillation and destabilized preformed αS fibrils. Cumulative evidence suggests that low-order αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds (myricetin (Myr), curcumin, rosmarinic acid (RA), nordihydroguaiaretic acid, and ferulic acid) on αS oligomerization. Using methods such as photo-induced cross-linking of unmodified proteins, circular dichroism spectroscopy, the electron microscope, and the atomic force microscope, we showed that Myr and RA inhibited αS oligomerization and secondary structure conversion. The nuclear magnetic resonance analysis revealed that Myr directly bound to the N-terminal region of αS, whereas direct binding of RA to monomeric αS was not detected. Electrophysiological assays for long-term potentiation in mouse hippocampal slices revealed that Myr and RA ameliorated αS synaptic toxicity by inhibition of αS oligomerization. These results suggest that Myr and RA prevent the αS aggregation process, reducing the neurotoxicity of αS oligomers. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds on α-synuclein (αS) oligomerization. Phenolic compounds, especially Myricetin (Myr) and Rosmarinic acid (RA), inhibited αS oligomerization and secondary structure conversion. Myr and RA ameliorated αS synaptic toxicity on the experiment of long-term potentiation. Our results suggest that Myr and RA prevent αS aggregation process and reduce the neurotoxicity of αS oligomers. Phenolic compounds are good candidates of disease modifying drugs for α-synucleinopathies.


Assuntos
Amiloide/efeitos dos fármacos , Antioxidantes/farmacologia , Fenóis/farmacologia , alfa-Sinucleína/efeitos dos fármacos , Animais , Cinamatos/farmacologia , Dicroísmo Circular , Ácidos Cumáricos/farmacologia , Curcumina/farmacologia , Depsídeos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Flavonoides/farmacologia , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração , Masoprocol/farmacologia , Camundongos , Microscopia de Força Atômica , Modelos Moleculares , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Polimerização/efeitos dos fármacos , Estrutura Secundária de Proteína , alfa-Sinucleína/química , Ácido Rosmarínico
11.
J Med Case Rep ; 9: 67, 2015 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-25889685

RESUMO

INTRODUCTION: Qing fei tang, which is used for various respiratory diseases, is useful for reducing relapse of aspiration pneumonia and bronchopneumonia in stroke, but the effect remains unknown in Parkinson's syndrome. We report two cases of Japanese patients with progressive supranuclear palsy and relapsing aspiration pneumonia and bronchopneumonia, which was successfully prevented by qing fei tang. CASE PRESENTATION: Two Japanese men with progressive supranuclear palsy and receiving total enteral feeding (patient one (66-years-old) and patient two (76-years-old)) had experienced recurrent aspiration pneumonia and bronchopneumonia, which was unresponsive to conventional therapy. The respiratory infection developed twice at intervals of two months in patient one, and nine times at almost monthly intervals in patient two. Thereafter, they were given qing fei tang. After administration of qing fei tang, the respiratory infection reoccurred only once; after 5.5 months for patient one, and six months for patient two. Both of our patients clearly showed a reduced incidence of respiratory infection. CONCLUSIONS: Both of our patients clearly showed a reduced incidence of respiratory infection after the administration of qing fei tang. Qing fei tang could be useful for the prevention of recurrent aspiration pneumonia and bronchopneumonia in progressive supranuclear palsy.


Assuntos
Broncopneumonia/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Pneumonia Aspirativa/tratamento farmacológico , Paralisia Supranuclear Progressiva/complicações , Idoso , Broncopneumonia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Aspirativa/etiologia
12.
J Neurol Sci ; 345(1-2): 231-5, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25060417

RESUMO

OBJECTIVE: To evaluate the long-term efficacy and safety of diflunisal in late-onset familial amyloid polyneuropathy (FAP) in a Japanese endemic area. METHODS: Consecutive six FAP patients (mean age: 65.8 ± 7.3 years) with a transthyretin (TTR) Val30Met mutation from an endemic area of late-onset FAP were prospectively recruited to an open label study with oral diflunisal (250 mg twice a day). We evaluated clinical symptoms, Kumamoto FAP score, modified body mass index (mBMI), Medical Research Council sum score, nerve conduction studies (NCS), electrocardiogram (ECG), ECG Holter monitor test, echocardiography, and (123)iodine-metaiodobenzylguanidine ((123)I-MIBG) myocardial scintigraphy. RESULTS: One patient ceased to take diflunisal because of hematuria which was reversible. The other five patients were treated with diflunisal for 3-5 (4.4 ± 0.9 years) years. Autonomic symptoms (orthostatic hypotension and gastrointestinal symptoms) disappeared after treatment in two of the four patients with the symptoms. Delayed heart to mediastinum ratio on (123)I-MIBG imaging, a marker of cardiac postganglionic sympathetic nerve function, increased during the three-year treatment. mBMI was maintained through observation period. While, motor and sensory symptoms, Kumamoto FAP scores, and data on NCS gradually deteriorated. CONCLUSION: Diflunisal might be effective especially for autonomic dysfunction in late-onset FAP with a TTR Val30Met mutation.


Assuntos
Neuropatias Amiloides Familiares/genética , Anti-Inflamatórios não Esteroides/uso terapêutico , Doenças do Sistema Nervoso Autônomo/tratamento farmacológico , Diflunisal/uso terapêutico , Mutação/genética , Pré-Albumina/genética , 3-Iodobenzilguanidina , Idoso , Neuropatias Amiloides Familiares/complicações , Doenças do Sistema Nervoso Autônomo/diagnóstico por imagem , Doenças do Sistema Nervoso Autônomo/etiologia , Eletrocardiografia , Feminino , Humanos , Japão , Masculino , Metionina/genética , Pessoa de Meia-Idade , Farmacogenética , Cintilografia , Compostos Radiofarmacêuticos , Valina/genética
13.
Intern Med ; 53(11): 1201-4, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24881749

RESUMO

We herein describe the case of an 81-year-old Japanese woman with neuroleptic malignant syndrome that occurred 36 days after the initiation of combination therapy with tiapride (75 mg/day) and tetrabenazine (12.5 mg/day) for Huntington's disease. The patient had been treated with tiapride or tetrabenazine alone without any adverse effects before the administration of the combination therapy. She also had advanced breast cancer when the combination therapy was initiated. To the best of our knowledge, the occurrence of neuroleptic malignant syndrome due to combination therapy with tetrabenazine and tiapride has not been previously reported. Tetrabenazine should be administered very carefully in combination with other neuroleptic drugs, particularly in patients with a worsening general condition.


Assuntos
Inibidores da Captação Adrenérgica/efeitos adversos , Doença de Huntington/tratamento farmacológico , Síndrome Maligna Neuroléptica/etiologia , Tetrabenazina/efeitos adversos , Cloridrato de Tiaprida/efeitos adversos , Adulto , Idoso de 80 Anos ou mais , Antipsicóticos/efeitos adversos , Neoplasias da Mama/complicações , Antagonistas de Dopamina/efeitos adversos , Quimioterapia Combinada/efeitos adversos , Feminino , Humanos , Doença de Huntington/complicações , Pessoa de Meia-Idade , Recidiva Local de Neoplasia
14.
Biochim Biophys Acta ; 1842(4): 646-53, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24440525

RESUMO

Amyloid ß-protein (Aß) aggregation is considered to be a critical step in the neurodegeneration of Alzheimer's disease (AD). In addition to Aß, many proteins aggregate into the amyloid state, in which they form elongated fibers with spines comprising stranded ß-sheets. However, the cross-seeding effects of other protein aggregates on Aß aggregation pathways are not completely clear. To investigate the cross-seeding effects of exogenous and human non-CNS amyloidogenic proteins on Aß aggregation pathways, we examined whether and how sonicated fibrils of casein, fibroin, sericin, actin, and islet amyloid polypeptide affected Aß40 and Aß42 aggregation pathways using the thioflavin T assay and electron microscopy. Interestingly, the fibrillar seeds of all amyloidogenic proteins functioned as seeds. The cross-seeding effect of actin was stronger but that of fibroin was weaker than that of other proteins. Furthermore, our nuclear magnetic resonance spectroscopic studies identified the binding sites of Aß with the amyloidogenic proteins. Our results indicate that the amyloidogenic proteins, including those contained in foods and cosmetics, contribute to Aß aggregation by binding to Aß, suggesting their possible roles in the propagation of Aß amyloidosis.


Assuntos
Peptídeos beta-Amiloides/química , Proteínas Amiloidogênicas/farmacologia , Amiloidose/etiologia , Benzotiazóis , Humanos , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica , Tiazóis/metabolismo
15.
Eur Neurol ; 71(3-4): 99-105, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24335185

RESUMO

OBJECTIVE: To examine whether there are clinical features in Japanese patients with both neurodegenerative diseases and cancers. METHODS: We analyzed the clinical characteristics of consecutive Japanese patients with neurodegenerative diseases during the past 5 years, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), dementia with Lewy bodies, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA). RESULTS: Out of 292 patients, 39 patients had cancers, including a past history, as follows: ALS, n = 16; PD, n = 8; PSP, n = 7; CBD, n = 1, and MSA, n = 7. About 10% of patients with neurodegenerative diseases developed cancer after onset of the disease; about 30% of patients with ALS, PD, or PSP occurring with cancers died of cancer. Gastric cancer was most common before the onset of ALS (62.5%) but did not develop after the onset of ALS. Conversely, PD patients frequently developed gastric cancers after the onset of neurological signs (60.0%) in spite of no cancer before the onset of PD. The proportion of breast cancer in MSA (45.5%) was significantly higher than in other neurodegenerative diseases. CONCLUSION: ALS, PD, or MSA patients with cancer showed clinical characteristics unique to each neurodegenerative disease in Japan compared to other countries.


Assuntos
Neoplasias/complicações , Neoplasias/epidemiologia , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
16.
J Neurosci Res ; 91(10): 1371-81, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23913715

RESUMO

The aggregation of ß-amyloid protein (Aß) and α-synuclein (αS) are hypothesized to be the key pathogenic event in Alzheimer's disease (AD) and Lewy body diseases (LBD), with oligomeric assemblies thought to be the most neurotoxic. Inhibitors of oligomer formation, therefore, could be valuable therapeutics for patients with AD and LBD. Here, we examined the effects of antiparkinsonian agents (dopamine, levodopa, trihexyphenidyl, selegiline, zonisamide, bromocriptine, peroxide, ropinirole, pramipexole, and entacapone) on the in vitro oligomer formation of Aß40, Aß42, and αS using a method of photo-induced cross-linking of unmodified proteins (PICUP), electron microscopy, and atomic force microscopy. The antiparkinsonian agents except for trihexyphenidyl inhibited both Aß and αS oligomer formations, and, among them, dopamine, levodopa, pramipexole, and entacapone had the stronger in vitro activity. Circular dichroism and thioflavin T(S) assays showed that secondary structures of Aß and αS assemblies inhibited by antiparkinsonian agents were statistical coil state and that their seeding activities had disappeared. The antiparkinsonian agents could be potential therapeutic agents to prevent or delay AD and LBD progression.


Assuntos
Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/efeitos dos fármacos , Antiparkinsonianos/farmacologia , alfa-Sinucleína/química , alfa-Sinucleína/efeitos dos fármacos , Dicroísmo Circular , Humanos , Microscopia de Força Atômica , Microscopia Eletrônica de Transmissão , Fragmentos de Peptídeos
18.
J Neurochem ; 122(5): 883-90, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22734715

RESUMO

Amyloid ß-protein (Aß) and α-synuclein (αS) are the primary components of amyloid plaques and Lewy bodies (LBs), respectively. Previous in vitro and in vivo studies have suggested that interactions between Aß and αS are involved in the pathogenesis of Alzheimer's disease and LB diseases. However, the seeding effects of their aggregates on their aggregation pathways are not completely clear. To investigate the cross-seeding effects of Aß and αS, we examined how sonicated fibrils or cross-linked oligomers of Aß40, Aß42, and αS affected their aggregation pathways using thioflavin T(S) assay and electron microscopy. Fibrils and oligomers of Aß40, Aß42, and αS acted as seeds, and affected the aggregation pathways within and among species. The seeding effects of αS fibrils were higher than those of Aß40 and Aß42 fibrils in the Aß40 and Aß42 aggregation pathways, respectively. We showed that Aß and αS acted as seeds and affected each other's aggregation pathways in vitro, which may contribute to our understanding of the molecular mechanisms of interactions between Alzheimer's disease and LB diseases pathologies.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/metabolismo , alfa-Sinucleína/metabolismo , Animais , Benzotiazóis , Cromatografia em Gel , Humanos , Microscopia Eletrônica de Varredura , Placa Amiloide/ultraestrutura , Ligação Proteica , Tiazóis/metabolismo
19.
Amyloid ; 19(3): 129-32, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22624582

RESUMO

OBJECTIVE: Familial amyloid polyneuropathy (FAP) is an autosomal dominant form of hereditary amyloidosis. Several studies reported coagulation factor X deficiency and excessive fibrinolysis in immunoglobulin light chain amyloidosis. However, few have investigated coagulation and fibrinolysis in FAP. The objective of this study was to determine abnormalities in plasma biomarkers of coagulation and fibrinolysis in FAP. METHODS: We prospectively recruited eight FAP patients with transthyretin mutations and ten age-matched control patients with other neuropathies in our university. We examined plasma biomarkers of coagulation and fibrinolysis including prothrombin time, activated partial thromboplastin time, fibrinogen, fibrin/fibrinogen degradation products, D-dimer, α2-antiplasmin, antithrombin, plasminogen, thrombin-antithrombin complex, plasmin-α2-antiplasmin complex, prothrombin fragment 1+2, and coagulation factor X. The Mann-Whitney U test was performed for statistical comparisons between FAP and control groups. RESULTS: FAP patients exhibited significantly decreased levels of coagulation factor X, plasminogen and α2-antiplasmin, and significantly increased levels of prothrombin fragment 1+2 compared to control patients. CONCLUSION: Our results indicate abnormalities of coagulation and fibrinolysis in FAP patients.


Assuntos
Neuropatias Amiloides Familiares/sangue , Transtornos da Coagulação Sanguínea/sangue , Fibrinólise , Adulto , Idoso , Estudos de Casos e Controles , Deficiência do Fator X , Feminino , Transtornos Hemorrágicos , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Plasminogênio/deficiência , Estudos Prospectivos , Precursores de Proteínas/sangue , Protrombina , Estatísticas não Paramétricas , alfa 2-Antiplasmina/deficiência
20.
Biochim Biophys Acta ; 1822(8): 1316-24, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22587837

RESUMO

Alzheimer's disease is characterized by the presence of extracellular deposits of amyloid, primarily composed of the amyloid ß-protein (Aß). A growing body of evidence indicates that oligomeric forms of Aß play a critical role in disease causation. Soybean isoflavones are flavonoids with an isoflavone backbone. Isoflavones have been reported to protect against Aß-induced neurotoxicity in cultured cell systems, the molecular mechanisms remain unclear. Our previous studies demonstrated that red wine-related flavonoids with a flavone backbone are able to inhibit Aß assembly and destabilize preformed Aß aggregates. Here, we show that isoflavones, especially glycitein and genistein, have anti-fibrillization, anti-oligomerization and fibril-destabilizing effects on Aß(1-40) and Aß(1-42)in vitro at physiological pH and temperature, by using nucleation-dependent polymerization monitored by thioflavin T fluorescence, atomic force microscopy, electron microscopy, and photo-induced cross-linking of unmodified proteins followed by SDS-PAGE. Our three-dimensional fluorescence spectroscopic analyses demonstrated that glycitein interacted with Aß monomers, oligomers and fibrils, indicating specific binding of glycitein to these Aß species. Glycitein also interacted with different Aß fragments (Aß(1-42), Aß(1-40), Aß(1-16) and Aß(25-35)), exhibiting the highest fluorescence enhancement with Aß(25-35). We speculated that glycitein's anti-amyloidogenic properties are specifically mediated by its binding to Aß monomers, oligomers and fibrils. Isoflavones may hold promise as a treatment option for preventative strategies targeting amyloid formation in Alzheimer's disease.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Isoflavonas/metabolismo , Isoflavonas/farmacologia , Fragmentos de Peptídeos/metabolismo , Peptídeos beta-Amiloides/química , Benzotiazóis , Humanos , Microscopia de Força Atômica , Microscopia Eletrônica/métodos , Fragmentos de Peptídeos/química , Glycine max/química , Espectrometria de Fluorescência/métodos , Tiazóis/química
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