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We conducted a multicenter, randomized, double-blind, placebo-controlled prospective trial examining a supplement containing ferulic acid and Angelica archangelica extract (Feru-guard ®) for mild cognitive impairment (MCI). In the intention-to-treat population, Mini-Mental State Examination (MMSE) scores were significantly better at 24 weeks (pâ=â0.041) in the active group. In the per protocol population, MMSE was significantly better in the active group at 24 weeks (pâ=â0.008), and mixed effect models for repeated measures (MMRM) showed significant difference (pâ=â0.016). ADAS-Jcog was significantly better at 24 (pâ=â0.035) and 48 weeks (pâ=â0.015) in the active group, and MMRM was significant (pâ=â0.031). Thus, Feru-guard ® may be useful for MCI.
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TMEM119 and purinergic receptor P2Y12 (P2RY12), which are not expressed by recruited peripheral blood macrophages, are proposed to discriminate microglia from macrophages. Therefore, we investigated the distribution patterns of microglia and macrophages in 10 concentric lesions from four autopsied Baló's disease cases and one neuromyelitis optica spectrum disorder (NMOSD) case, using quantitative immunohistochemistry for the markers TMEM119, P2RY12, CD68, CD163 and GLUT5. Three cases with Baló's disease had distal oligodendrogliopathy (DO) showing preferential loss of myelin-associated glycoprotein and early active demyelination in the outermost demyelinating layer (termed DMY-MO). In DMY-MO with DO, TMEM119-positive activated microglia expressing upregulated GLUT5 but markedly downregulated P2RY12 were significantly increased. These activated microglia expressed inducible nitric oxide synthase. Oligodendrocytes and their precursors showed apoptotic-like nuclear condensation in DMY-MO. TMEM119-negative and CD68/CD163-positive macrophages were distributed throughout the lesion center of DMY-MO with DO and these cells demonstrated foamy morphology only in the inner portion but not in the outer portion. In concentric demyelinating lesions from another Baló's case and lamellar demyelinating lesions in an NMOSD case, which had late active demyelination without DO, the densities of TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology were significantly increased in myelinated layers but not in demyelinating layers. In particular, in the NMOSD case, TMEM119-positive microglia were confined to the outer portion of the myelinated layers. CD68-positive macrophages with foamy morphology also expressing CD163 accumulated in myelinated as well as in demyelinated layers. These findings suggest that activated microglia expressing TMEM119 and GLUT5, but not P2RY12, are associated with apoptosis of oligodendrocytes in the leading edge of Baló's concentric lesions with DO, whereas TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology are associated with myelin preservation in concentric lesions without DO in Baló's disease and NMOSD. These two types of microglia appear to play distinct roles in the formation of concentric lesions.
Assuntos
Esclerose Cerebral Difusa de Schilder/patologia , Macrófagos/patologia , Microglia/patologia , Neuromielite Óptica/patologia , Adulto , Idoso , Esclerose Cerebral Difusa de Schilder/metabolismo , Feminino , Transportador de Glucose Tipo 5/metabolismo , Humanos , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Microglia/metabolismo , Neuromielite Óptica/metabolismo , Receptores Purinérgicos P2Y12/metabolismo , Adulto JovemRESUMO
BACKGROUND: In the treatment of Alzheimer's disease (AD), it is thought to be most effective to intervene at the earliest and mildest stages. For diagnosis at the earliest and mildest stages, it is desirable to use a biomarker that can be detected by a minimally invasive, cost-effective technique. Recent research indicates the potential clinical usefulness of plasma amyloid-ß (Aß) biomarkers in predicting brain Aß burden at an individual level. However, it is as yet unproven that accumulation of Aß necessarily leads to the development of AD. OBJECTIVE: Homocysteic acid (HCA) is useful as an early diagnostic marker for mild cognitive impairment (MCI), a pre-stage of AD. METHODS: We measured the concentration of HCA, tumor necrosis factor alpha, cortisol, tau, and phosphorylated tau (p-tau) in patients' plasma of 22 AD, 23 MCI, and 9 negative control (NC) cases. RESULTS: Plasma HCA was shown to be very high in areas under the receiver operating characteristic curves (AUC), distinguished between MCI and NC; when 0.116µM was chosen as the analyte concentration cut-off, the sensitivity was 95.7% and the specificity was 70%. CONCLUSION: Our results suggest that plasma HCA may be a useful indicator as an early diagnostic marker for MCI. HCA seems to be upstream from neurodegeneration in the AD pathology because it is known that an overactive NMDA receptor promotes amyloid polymerization and tau phosphorylation in AD.
Assuntos
Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico , Homocisteína/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Disfunção Cognitiva/psicologia , Feminino , Homocisteína/sangue , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Pathological aggregates of tau proteins accumulate in the brains of neurodegenerative tauopathies including Alzheimer's disease and frontotemporal lobar degeneration (FTLD-tau). Although immunotherapies of these disorders against tau are emerging, it is unknown whether nasal delivery, which offers many benefits over traditional approaches to vaccine administration, is effective or not for tauopathy. Here, we developed vaccination against a secreted form of pathological tau linked to FTLD-tau using a Sendai virus (SeV) vector infectious to host nasal mucosa, a key part of the immune system. Tau vaccines given as nasal drops induced tissue tau-immunoreactive antibody production and ameliorated cognitive impairment in FTLD-tau model mice. In vivo imaging and postmortem neuropathological assays demonstrated the suppression of phosphorylated tau accumulation, neurotoxic gliosis, and neuronal loss in the hippocampus of immunized mice. These findings suggest that nasal vaccine delivery may provide a therapeutic opportunity for a broad range of populations with human tauopathy.
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Extracts from Huperzia serrata (HS) function as a cholinesterase inhibitor and a glutamic acid receptor antagonist. We tested a supplement containing HS extracts, curcumin, and others in dementia patients and individuals with mild cognitive impairment (MCI) in an open label study. Most patients with Alzheimer's disease, dementia with Lewy bodies, and MCI individuals exhibited improvements in cognitive functions, as assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale Japanese version. The scores were significantly improved at 6-12 weeks compared with baseline scores (pâ=â0.007) and at 22-28 weeks (pâ=â0.004). Thus, this supplement may be administered to dementia patients as well as MCI individuals.
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Alcaloides/uso terapêutico , Transtornos Cognitivos/dietoterapia , Curcumina/uso terapêutico , Demência Vascular/dietoterapia , Suplementos Nutricionais , Sesquiterpenos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Medicamentos Biossimilares , Transtornos Cognitivos/complicações , Demência Vascular/complicações , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos , Resultado do TratamentoRESUMO
With the objective to improve the amyloid-ß (Aß) targeting immunotherapy, we investigated the safety and efficacy of an oral vaccine with recombinant adeno-associated virus vector carrying a signal sequence and Aß1-43 cDNA (rAAV/Aß) in old non-human primates, 12 African green and 10 cynomolgus monkeys. The enteric-dissolving coated capsules containing rAAV/Aß were orally administered once or twice, then monkeys' conditions were carefully observed with complete blood count and laboratory examinations of the sera. General conditions, food intake, water intake, stool conditions, body weight changes, and menstruation cycles were not significantly altered, and laboratory tests and pathological examinations of the systemic organs were unremarkable. Pathological examinations of the brain showed significant reduction of the amyloid plaque burden and intracellular Aß without inflammatory or hemorrhagic changes in the brain. However, soluble Aß and some Aß oligomers were increased in rAAV-treated monkey brains without changes of the neuronal density and vascular amyloidosis. Thus, this vaccine seems to be safe in general, but we must be cautious about the increase of Aß oligomers after vaccination. This vaccine may be recommended at a very early stage of Alzheimer's disease when little amyloid is deposited.
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Envelhecimento/patologia , Peptídeos beta-Amiloides/administração & dosagem , Encéfalo/patologia , Dependovirus , Fragmentos de Peptídeos/administração & dosagem , Placa Amiloide/tratamento farmacológico , Placa Amiloide/patologia , Administração Oral , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Chlorocebus aethiops , Feminino , Células HEK293 , Humanos , Macaca fascicularis , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/metabolismo , Vacinas/administração & dosagemRESUMO
Active and passive immunization of Alzheimer model mice with Aß showed clearance of aggregated amyloid ß deposits and improved memory and learning. Although human trial was halted because of autoimmune encephalitis, the trial revealed that immunization with Aß also deleted amyloid deposits in humans without clinical benefit. On these proof of concept, several clinical trials using monoclonal antibodies are on-going. Although solanezumab which recognizes Aß monomer turned out ineffective in the primary endpoint, it showed significant beneficial effect in mild AD cases in the secondary outcome. Solanezumab is now on a large scale phase III trial in mild AD cases in the world. If it turns out to be effective, it will be the first disease modifying drug for AD in a few years. However, since monoclonal antibodies are extremely expensive, less expensive and long acting active immunization will be widely accepted. More effective and sophisticated vaccines such as DNA vaccine and recombinant viral vaccines will be utilized in future.
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Doença de Alzheimer/terapia , Vacinas contra Alzheimer/uso terapêutico , Peptídeos beta-Amiloides/imunologia , Imunização , Doença de Alzheimer/imunologia , Animais , Ensaios Clínicos como Assunto , HumanosRESUMO
The truncated tau protein is a component of the neurofibrillary tangles found in the brains with tauopathies. However, the molecular mechanisms by which the truncated tau fragment causes neurodegeneration remain unknown. Tau pathology was recently suggested to spread through intercellular propagation, and required the formation of 'prion-like' species. We herein identified a new fragment of the tau protein that consisted of four binding domains and a C-terminal tail (Tau-CTF24), but lacked the N-terminal projection domain, and found that it increased with aging in tauopathy model mice (Tg601). Tau-CTF24-like fragments were also present in human brains with tauopathies. A mass spectroscopic analysis revealed that Tau-CTF24 was cleaved behind R242. The digestion of full-length tau (Tau-FL) by calpain produced Tau-CTF24 in vitro and calpain activity increased in old Tg601. Recombinant Tau-CTF24 accelerated heparin-induced aggregation and lost the ability to promote microtubule assembly. When insoluble tau from diseased brains or aggregated recombinant tau was introduced as seeds into SH-SY5Y cells, a larger amount of insoluble tau was formed in cells overexpressing Tau-CTF24 than in those overexpressing Tau-FL. Furthermore, lysates containing the Tau-CTF24 inclusion propagated to naive tau-expressing cells more efficiently than those containing the Tau-FL inclusion. Immunoblot and confocal microscopic analyses revealed that aggregated Tau-CTF24 bound to cells more rapidly and abundantly than aggregated Tau-FL. Our results suggest that Tau-CTF24 contributes to neurodegeneration by enhancing prion-like propagation as well as deteriorating the mechanisms involved in microtubule function.
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Príons/metabolismo , Tauopatias/metabolismo , Proteínas tau/metabolismo , Fatores Etários , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Calpaína/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microtúbulos/metabolismo , Emaranhados Neurofibrilares/genética , Emaranhados Neurofibrilares/metabolismo , Fosforilação , Príons/genética , Estrutura Terciária de Proteína , Tauopatias/genética , Proteínas tau/genéticaRESUMO
The imbalance between ß-amyloid (Aß) generation and clearance plays a fundamental role in the pathogenesis of Alzheimer's disease (AD). The sporadic form of AD is characterized by an overall impairment in Aß clearance. Immunotherapy targeting Aß clearance is believed to be a promising approach and is under active clinical investigation. Autophagy is a conserved pathway for degrading abnormal protein aggregates and is crucial for Aß clearance. We previously reported that oral vaccination with a recombinant AAV/Aß vaccine increased the clearance of Aß from the brain and improved cognitive ability in AD animal models, while the underlying mechanisms were not well understood. In this study, we first demonstrated that oral vaccination with rAAV/Aß decreased the p62 level and up-regulated the LC3B-II/LC3B-I ratio in APP/PS1 mouse brain, suggesting enhanced autophagy. Further, inhibition of the Akt/mTOR pathway may account for autophagy enhancement. We also found increased anti-Aß antibodies in the sera of APP/PS1 mice with oral vaccination, accompanied by elevation of complement factors C1q and C3 levels in the brain. Our results indicate that autophagy is closely involved in oral vaccination-induced Aß clearance, and modulating the autophagy pathway may be an important strategy for AD prevention and intervention.
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Doença de Alzheimer/metabolismo , Vacinas contra Alzheimer/administração & dosagem , Peptídeos beta-Amiloides/metabolismo , Autofagia/efeitos dos fármacos , Encéfalo/metabolismo , Fragmentos de Peptídeos/administração & dosagem , Administração Oral , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/administração & dosagem , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/efeitos dos fármacos , Dependovirus , Modelos Animais de Doenças , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Presenilina-1/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Recombinantes/administração & dosagem , Serina-Treonina Quinases TOR/metabolismoRESUMO
Huperzia serrata has been used as a Chinese folk medicine for many years. It contains huperzine A, which has a protective effect against memory deficits in animal models; however, it is unclear if H. serrata extract exerts any effects in Alzheimer's disease (AD) models. We used H. serrata collected in Japan and determined its huperzine A content using HPLC. We determined its inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. H. serrata extract (30 mg/kg/day) and donepezil (10 mg/kg/day) were orally administrated for 7 days. After repeated administration, we performed the Y-maze and passive avoidance tests. H. serrata extract contained 0.5% huperzine A; H. serrata extract inhibited AChE, but not BuChE. H. serrata extract ameliorated cognitive function in mice. These results indicate that Japanese H. serrata extract ameliorates cognitive function deficits by inhibiting AChE. Therefore, H. serrata extract may be valuable for the prevention or treatment of dementia in AD.
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Alcaloides/administração & dosagem , Inibidores da Colinesterase/administração & dosagem , Transtornos Cognitivos/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Sesquiterpenos/administração & dosagem , Acetilcolinesterase/biossíntese , Acetilcolinesterase/efeitos dos fármacos , Alcaloides/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Butirilcolinesterase/biossíntese , Butirilcolinesterase/efeitos dos fármacos , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/patologia , Huperzia/química , Japão , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/patologia , Camundongos , Extratos Vegetais/química , Escopolamina/toxicidade , Sesquiterpenos/químicaRESUMO
Excess manganese (Mn) in brain can be neurotoxic, implicated in several neurodegenerative disorders such as sporadic Alzheimer's disease (AD). However, little is known about the altered metal environment including elevated Mn in the progressive cognitive impairment of AD. Indeed, whether high Mn is associated with AD risk remains elusive. In the study, we recruited 40 Chinese elders with different cognitive statuses and investigated concentrations of Mn in whole blood and plasma amyloid-ß (Aß) peptides. Surprisingly, there were significant correlations of Mn with Mini-Mental State Examination score and Clinical Dementia Rating Scale score. In addition, plasma Aß peptides increased with elevated Mn. Further studies both in vitro and in vivo demonstrated dose-related neurotoxicity and increase of Aß by Mn treatment, which was probably caused by disrupted Aß degradation. These data suggested that high Mn may be involved in the progress of AD as an essential pathogenic factor.
Assuntos
Doença de Alzheimer/complicações , Transtornos Cognitivos/metabolismo , Manganês/efeitos adversos , Manganês/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Líquido Extracelular/efeitos dos fármacos , Líquido Extracelular/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , L-Lactato Desidrogenase/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Entrevista Psiquiátrica Padronizada , Camundongos , Camundongos Transgênicos , Mutação/genética , Neuroblastoma/patologia , Presenilina-1/genéticaRESUMO
Microglia are the main immunocompetent and phagocytic cells in Alzheimer's disease (AD). Bone marrow-derived microglia have been demonstrated to be more effective in antigen presentation and phagocytosis than inherent microglia in AD. Thus, microglia have received much attention in the pathogenesis of AD. The herbal medicine Juzen-taiho-to (JTT) has been reported to reduce ß-amyloid (Aß) burden in the mouse brain of an AD model. In this study, we explored the effects of JTT on the migration and differentiation of bone marrow-derived cells in the mouse brain of acutely induced AD. To chase bone marrow-derived cells, we made a chimeric mouse line in C57BL/6 by transplanting fresh bone marrow cells, isolated from the transgenic mice expressing enhanced green fluorescent protein gene. The chimeric mice were orally administrated with JTT or distilled water, and were left untreated or given intrahippocampal injection of fibrillar Aß 1-42 (fAß42) or vehicle. In the hippocampus of the vehicle-injected mouse, JTT treatment for 37 days caused a significant increase in the number of microglial cells. In the fAß42-injected mouse hippocampus, a larger number of bone marrow-derived cells were detected in JTT-treated mice than control mice in the non-neighboring regions of the fAß42-injected site but not around the injected site. These results suggest that JTT might contribute to the reduction of Aß burden and the immune surveillance in non-pathological as well as pathological brain regions. The results also implicate the therapeutic potential of JTT in AD.
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Peptídeos beta-Amiloides/efeitos adversos , Células da Medula Óssea/citologia , Transplante de Medula Óssea , Encéfalo/patologia , Diferenciação Celular , Medicamentos de Ervas Chinesas/uso terapêutico , Microglia/citologia , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Antígeno CD11b/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Galinhas , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Citometria de Fluxo , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Imuno-Histoquímica , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Fenótipo , Irradiação Corporal TotalRESUMO
Previous studies have shown a high prevalence of obstructive sleep apnea (OSA) among patients with Alzheimer's disease (AD). However, it is poorly assessed whether chronic intermittent hypoxia (CIH), which is a characteristic of OSA, affects the pathophysiology of AD. We aimed to investigate the direct effect of intermittent hypoxia (IH) in pathophysiology of AD in vivo and in vitro. In vivo, 15 male triple transgenic AD mice were exposed to either CIH or normoxia (5% O2 and 21% O2 every 10 min, 8 h/day for 4 weeks). Amyloid-ß (Aß) profile, cognitive brain function, and brain pathology were evaluated. In vitro, human neuroblastoma SH-SY5Y cells stably expressing wild-type amyloid-ß protein precursor were exposed to either IH (8 cycles of 1% O2 for 10 min followed by 21% O2 for 20 min) or normoxia. The Aß profile in the conditioned medium was analyzed. CIH significantly increased levels of Aß42 but not Aß40 in the brains of mice without the increase in hypoxia-inducible factor 1, alpha subunit (HIF-1α) expression. Furthermore, CIH significantly increased intracellular Aß in the brain cortex. There were no significant changes in cognitive function. IH significantly increased levels of Aß42 in the medium of SH-SY5Y cells without the increase in the HIF-1α expression. CIH directly and selectively increased levels of Aß42 in the AD model. Our results suggest that OSA would aggravate AD. Early detection and intervention of OSA in AD may help to alleviate the progression of the disease.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Oxigenoterapia Hiperbárica , Hipóxia/metabolismo , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Linhagem Celular Tumoral , Transtornos Cognitivos/etiologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroblastoma/patologiaRESUMO
Neuromyelitis optica (NMO) is associated with antibodies to aquaporin 4 (AQP4). We hypothesized that antibodies to AQP4 can be triggered by exposure to environmental proteins. We compared human AQP4 to plant and bacterial proteins to investigate the occurrence of significantly similar structures and sequences. High similarity to a known epitope for NMO-IgG, AQP4(207-232), was observed for corn ZmTIP4-1. NMO and non-NMO sera were assessed for reactivity to AQP4(207-232) and the corn peptide. NMO patient serum showed reactivity to both peptides as well as to plant tissue. These findings warrant further investigation into the role of the environment in NMO etiology.
Assuntos
Aquaporina 4/genética , Aquaporina 4/imunologia , Epitopos/imunologia , Mimetismo Molecular/imunologia , Neuromielite Óptica/imunologia , Sequência de Aminoácidos , Animais , Aquaporina 4/química , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Reações Cruzadas/imunologia , Escherichia coli , Humanos , Dados de Sequência Molecular , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/imunologia , Plasmodium falciparum , Estrutura Terciária de Proteína , Ovinos , Glycine max , Spinacia oleracea , NicotianaRESUMO
The voxel-based morphometry (VBM) technique using brain magnetic resonance imaging (MRI) objectively maps gray matter loss on a voxel-by-voxel basis after anatomic standardization. In patients with Alzheimer's disease (AD), reductions of gray matter volume, mainly in the medial temporal structures, have been reported; however, inhomogeneity and geometric distortion of the field intensity hampers the reproducibility of MRI. In the present study, we developed a novel computed tomography (CT)-based VBM method and used this technique to detect volume loss in AD patients as compared with normal controls. The results were compared with MRI-based VBM using the same subjects. Pittsburgh Compound B ((11)C-PIB) positron emission tomography (PET)/CT was performed and two experts in neuro-nuclear medicine judged whether regional amyloid ß load was consistent with a diagnosis of AD. Before the injection of (11)C-PIB, high-quality CT scans were obtained using the same PET/CT equipment. MRI was performed within a mean interval of 25.1 ± 8.2 days before the PET/CT scan. Using statistical parametric mapping 8 (SPM8), the extracted gray matter images from CT and MRI were spatially normalized using a gray matter template and smoothed using a Gaussian kernel. Group comparisons were performed using SPM8 between five (11)C-PIB-positive patients with probable AD and seven (11)C-PIB-negative age-matched controls with normal cognition. Gray matter volumes in the bilateral medial temporal areas were reduced in the AD group as compared with the cognitively normal group in both CT-based VBM (in the left; P < 0.0001, cluster size 2776 and in the right; P < 0.0001, cluster size 630) and MRI-based VBM (in the left; P < 0.0001, cluster size 381 and in the right, P < 0.0001, cluster size 421). This newly developed CT-based VBM technique can detect significant atrophy in the entorhinal cortex in probable AD patients as previously reported using MRI-based VBM. However, CT-VBM was more sensitive and revealed larger areas of significant atrophy than MR-VBM.
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Amyloid-ß protein (Aß) accumulates in the neurons of Alzheimer's disease (AD) patients at an early stage of the disease. Recently, we found that Aß with a toxic turn at positions 22 and 23 accumulates in neurons in AD brain. Here, we studied the accumulation of Aß, toxic turn Aß and high-molecular-weight Aß oligomers in presenilin 1 (PS1) gene-transfected SH-SY5Y cells as well as in the brains of 3xTg-AD mice and AD patients. Immunostaining revealed that accumulation of toxic turn Aß was promoted in G384A- and I143T-mutant PS1-transfected cells and further enhanced by co-transfection of cells with the Aß-precursor protein (AßPP) gene. In contrast, accumulation of high-molecular-weight Aß oligomers was promoted in mutant PS1 cells but attenuated by co-transfection of cells with the AßPP gene. Toxic turn Aß was detected in the neurons of 3xTg-AD mice aged 2 months, when the mice were cognitively unimpaired. In contrast, high-molecular-weight Aß oligomers were detected in the neurons of 7-month-old mice, when memory dysfunction is apparent. Furthermore, immunostaining and western blotting for Rab4, Rab6 and GRP78 revealed increased levels of these proteins in mutant PS1 cells and their accumulation in the neurons of 3xTg-AD mice. Remarkably, GRP78 immunoreactivity was increased at 2 months of age. Double-label immunostaining of AD brain revealed an apparent association between toxic turn Aß and GRP78, an endoplasmic reticulum (ER) stress marker. Intraneuronal accumulation of toxic turn Aß may be associated with ER stress in the brains of AD model mice and AD patients at an early stage.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Líquido Intracelular/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/genética , Animais , Células Cultivadas , Chaperona BiP do Retículo Endoplasmático , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Presenilina-1/genética , Transfecção , Proteínas tau/genéticaRESUMO
Based on the amyloid cascade hypothesis, immunotherapy targeting amyloid ß (Aß) for Alzheimer's disease (AD) has been developed. It was reported that active immunization using Aß peptide attenuates amyloid deposits and memory impairment in AD model mice. However, active immunization of patients with AD (AN-1792) was halted due to adverse effects in which a subset of patients developed meningoencephalitis. In order to avoid autoimmune encephalitis, passive immunotherapy using humanized monoclonal antibodies with specificity to Aß are in clinical trials. We also developed an anti-Aß monoclonal antibody 3.4A10, which react with AD brain-specific Aß oligomers. On the other hand, some studies showed that immunotherapy approach targeting tau could attenuate pathology in AD model mouse. Here we introduce a current trend of immunotherapy for AD.
Assuntos
Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/imunologia , Imunoterapia Ativa/métodos , Proteínas tau/imunologia , Doença de Alzheimer/imunologia , Animais , Humanos , CamundongosRESUMO
Homocysteic acid (HA) has been suggested as a pathogen in a mouse model of Alzheimer's disease (AD), 3xTg-AD. However, it is not established whether HA is involved in humans. We investigated the relationship between urinary HA levels and Mini-Mental State Examination (MMSE) scores in AD patients (n = 70) and non-AD controls (n = 34). We found a positive, statistically significant relationship between the two variables (the urinary HA level and MMSE score) (r = 0.31, p = 0.0008, n = 70). This relationship was stronger in females than males (r = 0.43, p = 0.005, n = 44 in females; r = 0.48, p = 0.02, n = 22 in males). The urinary HA levels were significantly different in AD patients than controls (AD: 8.7 ± 7.5, n = 70; non-dementia control: 13.3 ± 9.4, n = 34, p < 0.01). In addition, aging and smoking were found as lowering factors for urinary HA levels. Our preliminary study showed a negative, statistically significant relationship between blood HA (micromole) and urine HA levels (r = -0.6, p = 0.007, n = 19), and between blood HA levels and MMSE scores (r = -0.79, p = 0.0000518, n = 19). On the basis of these results, we speculate that reduced urinary excretion induces elevated HA levels in blood, resulting in cognitive dysfunctions. This study also suggests that HA may be a candidate of neurotoxins for uremic encephalopathy. Since amyloid-ß increases HA toxicity and HA is an agonist of N-methyl-D-aspartic acid (NMDA) receptor, we speculate that elevated blood HA affects the brain cognitive function through NMDA receptor-mediated toxicity in AD.
Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/urina , Homocisteína/análogos & derivados , Entrevista Psiquiátrica Padronizada , Idoso , Idoso de 80 Anos ou mais , Cromatografia Líquida de Alta Pressão , Eletroquímica , Feminino , Homocisteína/urina , Humanos , Masculino , Pessoa de Meia-Idade , Fumar/urina , Estatística como AssuntoRESUMO
Extensive aquaporin-4 (AQP4) loss without perivascular deposition of either activated complement or immunoglobulins is a characteristic of Baló's disease. Our aim in this study was to investigate the relationship between astrocytopathy and demyelination in Baló's disease, focusing on connexins (Cx), which form gap junctions among glial cells and myelin. Autopsied specimens from four cases that provided seven actively demyelinating concentric lesions infiltrated with numerous CD68(+) macrophages were immunohistochemically examined for the astrocyte markers glial fibrillary acidic protein (GFAP), AQP4, Cx43, Cx30 and megalencephalic leukoencephalopathy with subcortical cyst 1 (MLC1). Specimens were also stained for oligodendrocyte/myelin markers, namely Cx32, Cx47, myelin-associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein (OSP) and Nogo-A. Serum samples from six patients that had undergone magnetic resonance imaging, confirming a diagnosis of Baló's disease, were assayed for the presence of anti-Cx43, -Cx32 and -AQP4 antibodies. Despite the presence of numerous GFAP- and MLC1-positive astrocytes, there was a marked decrease in the levels of Cx43, Cx32 and Cx47. At the leading edges, Cx43 and AQP4 were mostly absent despite positive GFAP, MLC1, Cx32, Cx47, MOG, MAG, and OSP immunoreactivity. Of the six Baló's disease patients, none were positive for anti-Cxs or -AQP4 antibodies. Baló's disease is characterized by extensive loss of Cxs and AQP4, and a lack of auto-antibodies to Cxs and AQP4. Loss of Cx43 and AQP4 in the presence of other oligodendrocyte/myelin proteins at the leading edges suggests the possibility that auto-antibody-independent astrocytopathy may contribute to disease pathology via the disruption of astrocyte-oligodendrocyte/myelin interactions.
Assuntos
Astrócitos/metabolismo , Conexinas/metabolismo , Esclerose Cerebral Difusa de Schilder/metabolismo , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Adulto , Idoso , Aquaporina 4/imunologia , Aquaporina 4/metabolismo , Astrócitos/patologia , Autoanticorpos/metabolismo , Doenças Desmielinizantes/metabolismo , Esclerose Cerebral Difusa de Schilder/diagnóstico , Esclerose Cerebral Difusa de Schilder/imunologia , Esclerose Cerebral Difusa de Schilder/patologia , Feminino , Junções Comunicantes/metabolismo , Junções Comunicantes/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Imunoglobulinas/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas da Mielina/metabolismo , Bainha de Mielina/patologia , Glicoproteína Associada a Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito , Oligodendroglia/patologia , Adulto JovemRESUMO
Growing evidence suggests that decreased brain-derived neurotrophic factor (BDNF) levels are associated with Alzheimer's disease (AD) pathogenesis. Therefore, BDNF gene therapy is considered to be a promising therapeutic strategy for treating AD. Sendai virus (SeV) is a type I parainfluenza virus that does not interact with host chromosomes because of its strict cytoplasmic life cycle. Although SeV is nonpathogenic in primates, including humans, its infectivity for neurons is strong. Here we demonstrate that SeV vectors effectively infected neurons, even though they were injected into subcortical white matter. Moreover, SeV vectors significantly induced BDNF expression, ameliorating synaptic degeneration and memory deficits in a transgenic mouse model of AD (Tg2576). This is the first study to demonstrate that viral vector administration in white matter is sufficient to restore cognitive function in vivo. These results also support the feasibility of using SeV vectors for gene therapy targeting the brain.