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1.
Neurotox Res ; 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31209785

RESUMO

Parkinson's disease (PD) is attributed to interactions among genes and environmental and lifestyle factors, but the genetic architecture of PD is complex and not completely understood. To evaluate whether the genetic profile modifies PD development and cerebrospinal fluid (CSF) pathological biomarkers, we enrolled 418 PD patients and 426 age- and sex-matched normal controls. Forty-six single nucleotide polymorphisms (SNPs) that were reported to be significantly associated with PD in large-scale genome-wide association studies (GWASs) were genotyped and analysed. The alleles associated with PD were used to build polygenic risk score (PRS) models to represent polygenic risk. The Cox proportional hazards model and receiver operating characteristic (ROC) analyses were used to evaluate the prediction value of the PRS for PD risk and age at onset. The CSF α-synuclein levels were measured in a subgroup of control subjects (n = 262), and its relationship with the PRS was analysed. We found that some SNPs identified from other populations had significant correlations with PD in our Chinese cohort. The PRS we built had prediction value for PD risk and age at onset. The CSF α-synuclein level had no correlation with the PRS in normal subjects.

2.
J Alzheimers Dis ; 63(1): 139-147, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29578485

RESUMO

The p75 neurotrophin receptor (p75NTR) is an amyloid-ß (Aß) receptor that both mediates Aß neurotoxicity and regulates Aß production and deposition, thus playing an important role in the pathogenesis of Alzheimer's disease (AD). The extracellular domain of p75NTR (p75ECD), consisting of four cysteine-rich repeat domains (CRDs), was recently reported to be an endogenous anti-Aß scavenger to block p75NTR-mediated neuronal death and neurite degeneration signaling of Aß and pro-neurotrophins. Identification of the specific Aß binding domains of p75NTR is crucial for illuminating their interactions and the etiology of AD. CRDs of p75ECD were obtained by expression of recombinant plasmids or direct synthesis. Aß aggregation inhibiting test and immunoprecipitation assay were applied to locate the specific binding domains of Aß to p75ECD. The Aß neurotoxicity antagonistic effects of different CRDs were examined by cytotoxicity experiments including neurite outgrowth assay, propidium iodide (PI) staining, and MTT assay. In the Aß aggregation inhibiting test, the fluorescence intensity in the CRD2 and CRD4 treatment groups was significantly lower than that in the CRD1 and CRD3 treatment groups. Immunoprecipitation assay and western blot confirmed that Aß could bind to CRD2 and CRD4. Besides, CRD2 and CRD4 antagonized Aß neurotoxicity suggested by longer neurite length, less PI labelled cells, and higher cell viability than the control group. Our results indicate that CRD2 and CRD4 are Aß binding domains of p75NTR and capable of antagonizing Aß neurotoxicity, and therefore are potential therapeutic targets to block the interaction of Aß and p75NTR in the pathogenesis of AD.

3.
J Alzheimers Dis ; 58(3): 919-925, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28505975

RESUMO

Previous studies have suggested that cardiovascular functions might play a critical role in Alzheimer's disease (AD) pathogenesis. However, the relationship among heart function, blood flow of cerebral vessels, and AD remains unclear. In the present study, AD patients (n = 34) and age- and gender-matched cognitively normal controls (n = 34) were recruited. Demographic and comorbidity information was collected. The ejection fraction was measured using echocardiography, and the mean velocity, pulsatility index (PI), and resistance index (RI) of the basilar artery (BA), left terminal internal carotid artery (LTICA), and right terminal internal carotid artery (RTICA) were measured using transcranial Doppler. The data of lacunae, white matter changes, and plaques in the aortic arch and carotid arteries were collected from brain magnetic resonance imaging and computed tomography angiography images. Compared with normal controls, AD patients had lower ejection fractions and cerebral blood flow velocities and higher RI and PI in the BA, LTICA, and RTICA, as well as more plaques in the aortic and carotid arteries. In the multivariate logistic regression analysis, the ejection fraction and the mean velocity of the BA and LTICA were independently associated with AD after adjusting for age, gender, education, vascular risk factors, arterial plaques, and brain ischemic lesions detected in the brain images. These findings suggest that heart function and vascular condition may play important roles in AD pathogenesis. Improving cardiovascular functions could be a promising approach for the prevention and treatment of AD.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Sistema Cardiovascular/diagnóstico por imagem , Sistema Cardiovascular/fisiopatologia , Idoso , Velocidade do Fluxo Sanguíneo , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Circulação Cerebrovascular , Comorbidade , Eletrocardiografia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fluxo Sanguíneo Regional , Volume Sistólico , Ultrassonografia Doppler Transcraniana
4.
Mol Neurobiol ; 54(3): 2338-2344, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-26957302

RESUMO

Amyloid-beta (Aß) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Clearance of Aß is a promising therapeutic strategy for AD. We have previously demonstrated that peripheral organs play important roles in the clearance of brain-derived Aß. In the present study, we recruited 46 patients with liver cirrhosis and 46 normal controls and found that plasma Aß40 and Aß42 levels were significantly higher in the cirrhosis patients than in the normal controls. Notably, cirrhosis patients with hepatitis B virus (HBV) infection had higher plasma Aß40 and Aß42 levels than HBV-negative cirrhosis patients. Besides, cirrhosis patients had significantly higher plasma levels of interleukin-1ß (IL-1ß) and IL-6. Plasma tumor necrosis factor α (TNF-α) and interferon-γ (IFN-γ) levels were not significantly different between the groups. Moreover, we found significant correlations of hepatic functions with plasma Aß40 and Aß42 levels. Plasma IL-6 levels were also significantly correlated with plasma Aß40 levels. However, in the linear regression model, we found significant correlation of plasma Aß40 levels with hepatic functions, but not with plasma IL-6 levels. Our results indicate that the hepatic dysfunctions might result in decreased peripheral Aß clearance by the liver. Protecting hepatic functions might be helpful for the clearance of brain-derived Aß in the blood.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/sangue , Encéfalo/metabolismo , Fígado/metabolismo , Idoso , Doença de Alzheimer/patologia , Feminino , Humanos , Interferon gama/sangue , Interleucina-1beta/sangue , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/metabolismo , Fator de Necrose Tumoral alfa/sangue
5.
J Neurochem ; 138(1): 163-73, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26991827

RESUMO

The neurotrophin receptor p75 (p75NTR) is a receptor for amyloid-beta (Aß) and mediates Aß-induced neurodegenerative signals. The ectodomain of p75NTR (p75ECD) is a physiological protective factor against Aß in Alzheimer's disease (AD). We have previously demonstrated that the shedding of p75ECD from the cell surface is down-regulated in AD brains and restoration of the p75ECD level in the brain, through intracranial administration of p75ECD by adeno-associated virus vectors, attenuates AD-like pathologies in an AD mouse model. In this study, we further investigated the feasibility and efficacy of peripheral administration of AAV-p75ECD on brain amyloid burden and associated pathogenesis. We found that intramuscular delivery of AAV-p75ECD increased the level of p75ECD in the blood, significantly improved the behavioral phenotype of amyloid precursor protein/PS1 transgenic mice, and reduced brain amyloid burden, attenuated Tau hyperphosphorylation, and neuroinflammation. Furthermore, intramuscular delivery of AAV-p75ECD was well tolerated. Our results indicate that peripheral delivery of p75ECD represents a safe and effective therapeutic strategy for AD. The ectodomain of p75NTR (p75ECD) is a physiological protective factor against amyloid-beta (Aß) in Alzheimer's disease (AD). Intramuscular delivery of AAV-p75ECD increased the p75ECD levels in the blood, reduced brain amyloid burden through a 'peripheral sink' mechanism and alleviates AD-type pathologies. Peripheral delivery of p75ECD represents a promising therapeutic strategy for AD.


Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Transtornos Cognitivos/terapia , Receptor de Fator de Crescimento Neural/química , Receptor de Fator de Crescimento Neural/metabolismo , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Transtornos Cognitivos/genética , Dependovirus/genética , Modelos Animais de Doenças , Vetores Genéticos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Injeções Intramusculares , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Presenilina-1/genética , Receptor de Fator de Crescimento Neural/genética , Transdução Genética
6.
Neurotox Res ; 29(2): 256-66, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26707129

RESUMO

Alzheimer's disease (AD) is the most common form of dementia among the elderly, characterized by parenchymal and vascular beta-amyloid (Aß) burden, tau pathology, neuroinflammation, and loss of neurons and synapses. There is a clear sex difference in the prevalence of AD. However, sex differences in AD-type pathologies have not been systematically documented. Applying 12-month-old female and male APP/PS1 mice as a model, we investigated the sex dimorphism in these major pathological indices. Compared with male APP/PS1 mice, the females exhibited higher parenchymal Aß burdens, with the sex difference in hippocampus being the most significant. Female APP/PS1 mice had more severe cerebral amyloid angiopathy and subsequent microhemorrhage. In addition, female APP/PS1 mice also showed higher levels of phosphorylated tau and proinflammatory cytokines, more severe astrocytosis and microgliosis, and greater neuronal and synaptic degenerations. The present study systematically described a sex dimorphism in AD-type pathologic indices, suggesting that gender should be taken into account in designing studies involving these pathological indices and when interpreting the relevant findings in those studies.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Caracteres Sexuais , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/irrigação sanguínea , Angiopatia Amiloide Cerebral/metabolismo , Angiopatia Amiloide Cerebral/patologia , Modelos Animais de Doenças , Encefalite/metabolismo , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/patologia , Fosforilação , Presenilina-1/genética , Sinapses/metabolismo , Sinapses/patologia , Proteínas tau/metabolismo
7.
J Neuroinflammation ; 12: 153, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26311039

RESUMO

BACKGROUND: Senile plaques consisting of amyloid-beta (Aß) are the major pathological hallmark of Alzheimer's disease (AD) and have been the primary therapeutic target. Immunotherapies, which are designed to remove brain Aß deposits, increased levels of soluble Aß and accelerated brain atrophy in some clinical trials, suggesting that the solubilization of Aß deposition might facilitate the formation of more toxic Aß oligomers and enhance neurotoxicity. METHODS: The capacity of antibodies against different epitopes of Aß to disaggregate preformed Aß fibrils was investigated. The co-incubation of antibodies and Aß fibrils was then tested for neurotoxicity both in vitro and in vivo. RESULTS: After the incubation of preformed Aß fibrils with the N-terminal antibody 6E10, the fibrils were decreased, while the oligomers, mostly dimers and trimers, were significantly increased. However, no such effects were observed for antibodies targeting the middle domain (4G8) and C-terminus of Aß (8G7). The co-incubates of preformed Aß fibrils with 6E10 were more neurotoxic, both in vitro and in vivo, than the co-incubates with 4G8 and 8G7. CONCLUSIONS: Our results indicate that the antibody targeting the N-terminus of Aß promoted the transformation of Aß from fibrils into oligomers and increased neurotoxicity. Immunotherapies should take into consideration the enhanced neurotoxicity associated with the solubilization of Aß deposits by antibodies against the Nterminus of Aß.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Anticorpos/efeitos adversos , Apoptose/efeitos dos fármacos , Síndromes Neurotóxicas , Fragmentos de Peptídeos/imunologia , Peptídeos beta-Amiloides/imunologia , Análise de Variância , Animais , Anticorpos/uso terapêutico , Caspase 3/metabolismo , Modelos Animais de Doenças , Humanos , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Neuritos/efeitos dos fármacos , Neuritos/patologia , Neuritos/ultraestrutura , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Fragmentos de Peptídeos/metabolismo , Fosfopiruvato Hidratase/metabolismo , Placa Amiloide/patologia
8.
Neurotox Res ; 28(4): 346-51, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26243505

RESUMO

Chronic obstructive pulmonary disease (COPD) is associated with cognitive decline, but the molecular link between COPD and dementia or Alzheimer's disease (AD) remains unclear. This study was aimed to investigate whether serum Aß levels are correlated with COPD. 77 cognitively normal COPD patients and 45 age- and gender-matched normal controls were admitted to the study. Serum Aß40 and Aß42 levels were measured using ELISA kits. Serum C-reactive protein (CRP), interleukin 6 (IL-6), and procalcitonin (PCT) measurements were done using standard laboratory methods. Pulmonary function tests were performed to assess the pulmonary function and determine the degree of lung damage. Significantly increased levels of serum Aß40, Aß42, and total Aß levels were found in patients with COPD in comparison with normal controls. In COPD patients, serum Aß levels were higher in subjects with serum CRP, IL-6, and PCT upper the limit of normal. Moreover, serum Aß levels were dramatically higher in COPD patients with worse pulmonary function. Our study suggests that cognitively normal COPD patients may undergo AD-related pathological changes, and COPD might facilitate AD-type pathogenesis.


Assuntos
Peptídeos beta-Amiloides/sangue , Doença Pulmonar Obstrutiva Crônica/sangue , Idoso , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Calcitonina/sangue , Peptídeo Relacionado com Gene de Calcitonina , Feminino , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Precursores de Proteínas/sangue , Testes de Função Respiratória
9.
Parkinsonism Relat Disord ; 21(8): 877-81, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26037459

RESUMO

INTRODUCTION: The etiology of Parkinson's disease (PD) remains unclear. The aim of this study was to examine the association between common pathogenic infections and PD. METHODS: Antibody titers to common infectious pathogens including cytomegalovirus (CMV), Epstein Barr virus (EBV),herpes simplex virus type-1 (HSV-1), Borrelia burgdorferi (B. burgdorferi), Chlamydophila pneumoniae (C. pneumoniae) and Helicobacter pylori (H. pylori) were measured by ELISA in serum of 131 PD patients and 141 normal controls. Infectious burden (IB) was defined as a composite serologic measure of exposure to these common pathogens. RESULTS: Seropositivities toward zero-two, three-four and five-six of these pathogens were found in 11%, 74% and 15% of normal controls while in 4%, 61% and 35% of PD patients, respectively. IB, bacterial burden and viral burden were independently associated with PD. Schwab and England (S&E) scores were negatively correlated with IB in patients with PD. Serum α-synuclein protein levels and inflammatory cytokines (interleukin-1ß and interleukin-6) in individuals with higher IB were also significantly higher. CONCLUSIONS: IB consisting of CMV, EBV, HSV-1, B. burgdorferi, C. pneumoniae and H. pylori is associated with PD. This study supports the role of infection in the etiology of PD.


Assuntos
Anticorpos Antibacterianos/sangue , Anticorpos Antivirais/sangue , Bactérias Gram-Negativas/imunologia , Herpesviridae/imunologia , Interleucina-1beta/sangue , Interleucina-6/sangue , Doença de Parkinson/sangue , alfa-Sinucleína/sangue , Idoso , Borrelia burgdorferi/imunologia , Estudos de Casos e Controles , Chlamydophila pneumoniae/imunologia , Citomegalovirus/imunologia , Feminino , Helicobacter pylori/imunologia , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 4/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
10.
Proc Natl Acad Sci U S A ; 112(16): 5225-30, 2015 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-25847999

RESUMO

Alzheimer's disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-ß (Aß) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Aß aggregation and attenuating Aß-induced oxidation in vitro. When given before or after the onset of Aß deposition via i.p. injection, Edaravone substantially reduces Aß deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antipirina/análogos & derivados , Transtornos Cognitivos/tratamento farmacológico , Administração Oral , Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Amiloide/metabolismo , Peptídeos beta-Amiloides/toxicidade , Animais , Antipirina/administração & dosagem , Antipirina/química , Antipirina/farmacologia , Antipirina/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Linhagem Celular , Transtornos Cognitivos/complicações , Transtornos Cognitivos/patologia , Dendritos/efeitos dos fármacos , Dendritos/patologia , Edaravone , Humanos , Inflamação/patologia , Camundongos Transgênicos , Neurotoxinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Presenilina-1/metabolismo , Agregação Patológica de Proteínas/complicações , Agregação Patológica de Proteínas/tratamento farmacológico , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas tau/metabolismo
11.
Neurotox Res ; 27(3): 292-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25612546

RESUMO

Mounting evidence suggests that ischemic stroke (IS) is associated with Alzheimer's disease (AD). IS and vascular risk factors increase the risk for AD. However, whether AD pathologies exist in IS and the effects of these pathologies on stroke remain unknown. In the present study, we aimed to investigate the alterations of serum Aß after acute IS (AIS), and its correlations with the neurological deficits, infarction volume, and site after stroke. AIS patients (n = 35) were recruited within 24 h of symptom onset. Age- and gender-matched AD patients (n = 48) and cognitively normal controls (NC, n = 37) were also enrolled. Serum Aß40 and Aß42 and the National Institute of Health Stroke Scale Score (NIHSS) were measured on day 1, 3, and 7 after stroke onset. We found that serum Aß40 and Aß42 levels were increased at day 1 and reached peak levels at day 3, and decreased to pre-stroke levels at day 7. Serum Aß40 levels at day 1 were correlated with the NIHSS scores and infarction volume of AIS patients. Serum Aß42 levels at day 1 were significantly higher in IS patients with dominant gray matter infarction. Serum Aß40 levels at day 1 were predictive for NIHSS at day 7. Our results indicate that AIS can induce the generation of Aß in the brain, which may in turn be involved in the pathogenesis of neurological deficits after stroke. Serum Aß might be predictive for the short-term neurological deficits after AIS.


Assuntos
Peptídeos beta-Amiloides/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/psicologia , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/psicologia , Doença Aguda , Adulto , Idoso , Encéfalo/patologia , Isquemia Encefálica/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Acidente Vascular Cerebral/complicações
12.
Neurotox Res ; 27(3): 284-91, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25631235

RESUMO

Amyloid precursor protein (APP) is cleaved by ß-secretase and γ-secretase complex, and subsequently generates amyloid-ß peptide (Aß). The Aß cascade is widely accepted as playing a role in the pathogenesis Alzheimer's disease (AD). Meanwhile, procession of APP by α-secretase (mainly a disintegrin and metalloproteinase 10, ADAM10) precludes Aß production, and produces soluble APP-α which is considered to be neuroprotective against AD. To explore the relationship between APP, ADAM10 gene polymorphism and sporadic AD (sAD), we conducted a case-control study in a Chinese Han cohort including 200 sAD patients and 243 control participants. Four target single nucleotide polymorphisms (SNPs) in or near the promoter of the APP gene and two in the promoter of the ADAM10 gene were selected and genotyped with a polymerase chain reaction-ligase detection reaction method. After adjustments for age, sex, and APOE ε4 status, only one target SNP, rs463946 was associated with the risk of sAD in the dominant (OR 1.52, 95 % CI 1.01-2.29, P = 0.045) and overdominant models (OR 1.59, 95 % CI 1.04-2.43, P = 0.031); the results also showed a borderline association of rs364048 (OR 1.53, 95 % CI 1.00-2.34, P = 0.048) and rs466433 (OR 1.53, 95 % CI 1.00-2.34, P = 0.048) with the risk of sAD in the overdominant model. However, these associations did not remain after multiple comparison correction. As for the ADAM10 gene, the two target SNPs (rs514049 and rs653765) were not associated with the risk of sAD either. No significant association was found between different haplotypes of the two genes and the risk of sAD. Conclusively, we did not find the association between APP, ADAM10 gene polymorphism, and the risk of sAD in our cohort of Chinese Han people.


Assuntos
Proteínas ADAM/genética , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/genética , Precursor de Proteína beta-Amiloide/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Proteína ADAM10 , Idoso , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Masculino , Fatores de Risco
13.
Mol Neurobiol ; 52(1): 115-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25119777

RESUMO

Amyloid-beta (Aß) plays a central role in the pathogenesis of Alzheimer's disease (AD), and it is a major therapeutic target for AD. It is proposed that removal of Aß in blood can facilitate Aß clearance from the brain, representing a promising therapeutic approach for AD. However, the efficacy and mechanisms for Aß clearance by peripheral organs and tissues remain largely unknown. In the present study, 47 chronic kidney disease (CKD) patients (16 newly diagnosed patients who had never been dialyzed and 31 patients who were receiving dialysis) and 43 normal controls (NC) were enrolled. We found that serum Aß levels were significantly higher in CKD patients than NC. CKD patients who were receiving dialysis had lower serum Aß levels than patients without receiving dialysis, being comparable to NC. Furthermore, serum Aß levels were correlated with renal functions reflected by estimated glomerular filtration rate (eGFR) and residual GFR (rGFR). Our study suggests that kidney is involved in peripheral clearance of Aß, and dialysis might be a potential therapeutic approach of Aß removal.


Assuntos
Peptídeos beta-Amiloides/sangue , Rim/metabolismo , Demografia , Feminino , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia
14.
Mol Neurobiol ; 51(3): 1271-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24986007

RESUMO

Insufficient neurotrophic support increases the risk for developing Alzheimer's disease (AD). Mounting evidence has confirmed the association of brain-derived neurotrophic factor (BDNF) and apolipoprotein E (ApoE) with AD. As both BDNF and ApoE are suggested to be involved in modulating brain integrity, the present study is aiming to investigate the associations between these two factors. In this study, 110 AD patients and 120 cognitively normal controls (NC) were recruited for measurement of serum BDNF levels and ApoE genotyping. Serum BDNF levels in the AD group were significantly lower than that in the NC group, reflecting insufficient neurotrophic supply in AD patients. We further found that ApoE ε4+/- and ε4+/+ subjects had significantly lower serum BDNF levels than ε4-/- subjects in the whole cohort and the NC group, suggesting altered BDNF metabolism in ApoE ε4 carriers. Further analysis indicated possible interactions between ApoEε4 and BDNF in their co-effects on AD and mini-mental state examination (MMSE) scores. Our findings imply that the possible involvement of ApoE ε4 in BDNF metabolism might be another molecular mechanism underlying the contribution of ApoE ε4 to the development of AD.


Assuntos
Doença de Alzheimer/metabolismo , Apolipoproteína E4/metabolismo , Fator Neurotrófico Derivado do Encéfalo/sangue , Encéfalo/metabolismo , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Cognição/fisiologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
15.
Mol Neurobiol ; 51(1): 1-7, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24733588

RESUMO

Amyloid-beta (Aß) is suggested to play a causal role in the pathogenesis of Alzheimer's disease (AD). Immunotherapies are among the most promising Aß-targeting therapeutic strategies for AD. But, to date, all clinical trials of this modality have not been successful including Aß vaccination (AN1792), anti-Aß antibodies (bapineuzumab, solanezumab and ponezumab), and intravenous immunoglobulin (IVIG). We propose that one reason for the failures of these clinical trials may be the adverse effects of targeting the central clearance of amyloid plaques. The potential adverse effects include enhanced neurotoxicity related to Aß oligomerization from plaques, neuroinflammation related to opsonized Aß phagocytosis, autoimmunity related to cross-binding of antibodies to amyloid precursor protein (APP) on the neuron membrane, and antibody-mediated vascular and neuroskeletal damage. Overall, the majority of the adverse effects seen in clinical trials were associated with the entry of antibodies into the brain. Finally, we propose that peripheral Aß clearance would be effective and safe for future Aß-targeting therapies.


Assuntos
Doença de Alzheimer/sangue , Peptídeos beta-Amiloides/sangue , Encéfalo/patologia , Doença de Alzheimer/imunologia , Doença de Alzheimer/terapia , Encéfalo/metabolismo , Humanos , Imunoterapia , Modelos Biológicos
16.
Neurotox Res ; 26(3): 211-5, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24737487

RESUMO

This study has identified a gene mutation in a Chinese family with Alzheimer's disease (AD). Family members were screened by a set of medical examinations and neuropsychological tests. Their DNA was extracted from blood cells and sequenced for gene mutation in the amyloid precursor protein (APP), the presenilin 1 (PS1) and the presenilin 2 (PS2) genes. Genetic analysis showed that the AD patients in the family harbored a T to G missense mutation at the position 314 in exon 4 of the PS1 gene, resulting in a change of F105C in amino acid sequence. Clinical manifestation of these patients included memory loss, counting difficulty, personality change, disorientation, dyscalculia, agnosia, aphasia, and apraxia, which was similar to that of the familial AD (FAD) patients harboring other PS1 mutations. We intend to add a novel mutation F105C of the PS1 gene to the pool of FAD mutations. With the current available genetic data, mutations of the PS1 gene account for the majority of gene mutations in Chinese FAD.


Assuntos
Doença de Alzheimer/genética , Mutação de Sentido Incorreto , Presenilina-1/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Grupo com Ancestrais do Continente Asiático , Encéfalo/patologia , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Linhagem
17.
Drug Discov Today ; 18(23-24): 1212-20, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23954180

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disorder among older people. However, no cure or disease-modifying treatments are currently available, and the molecular and cellular mechanisms responsible for the etiology of AD remain under debate. Recent studies suggest that the immune system has a crucial role in AD pathogenesis and, thus, immunotherapy might be a promising new treatment. Here, we review the roles of the immune system in AD pathogenesis as well as recent developments in immunotherapy for AD. Furthermore, we hypothesize that age-related immune dysregulation, which might be a consequence of the age-associated chronic inflammation known as 'inflammaging', significantly contributes to AD pathogenesis. Finally, we propose various immunological mechanisms for the development of safe and effective therapies for AD.


Assuntos
Doença de Alzheimer/terapia , Desenho de Drogas , Imunoterapia/métodos , Idoso , Doença de Alzheimer/imunologia , Doença de Alzheimer/fisiopatologia , Animais , Doença Crônica , Humanos , Sistema Imunitário/patologia , Inflamação/fisiopatologia , Inflamação/terapia
18.
J Neurochem ; 127(2): 152-62, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23895422

RESUMO

Sortilin, a Golgi sorting protein and a member of the VPS10P family, is the co-receptor for proneurotrophins, regulates protein trafficking, targets proteins to lysosomes, and regulates low density lipoprotein metabolism. The aim of this study was to investigate the expression and regulation of sortilin in Alzheimer's disease (AD). A significantly increased level of sortilin was found in human AD brain and in the brains of 6-month-old swedish-amyloid precursor protein/PS1dE9 transgenic mice. Aß42 enhanced the protein and mRNA expression levels of sortilin in a dose- and time-dependent manner in SH-SY5Y cells, but had no effect on sorLA. In addition, proBDNF also significantly increased the protein and mRNA expression of sortilin in these cells. The recombinant extracellular domain of p75(NTR) (P75ECD-FC), or the antibody against the extracellular domain of p75(NTR), blocked the up-regulation of sortilin induced by Amyloid-ß protein (Aß), suggesting that Aß42 increased the expression level of sortilin and mRNA in SH-SY5Y via the p75(NTR) receptor. Inhibition of ROCK, but not Jun N-terminal kinase, suppressed constitutive and Aß42-induced expression of sortilin. In conclusion, this study shows that sortilin expression is increased in the AD brain in human and mice and that Aß42 oligomer increases sortilin gene and protein expression through p75(NTR) and RhoA signaling pathways, suggesting a potential physiological interaction of Aß42 and sortilin in Alzheimer's disease.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/biossíntese , Peptídeos beta-Amiloides/fisiologia , Fragmentos de Peptídeos/fisiologia , Receptor de Fator de Crescimento Neural/biossíntese , Proteína rhoA de Ligação ao GTP/metabolismo , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/biossíntese , Animais , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/genética , Presenilina-1/biossíntese , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologia
19.
Neurosci Lett ; 550: 55-9, 2013 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-23831349

RESUMO

Alzheimer's disease (AD) is characterized by the degeneration of basal forebrain cholinergic neurons, whose survival and function are affected by neurotrophins and their receptors. The impaired signaling pathway of brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) is considered to play an important role in AD pathogenesis. To explore the association of polymorphisms within the NTRK2 gene (encoding TrkB) and sporadic AD (sAD), a case-control study was conducted in a Chinese Han cohort including 216 sAD patients and 244 control participants. Five single nucleotide polymorphisms (SNPs), with four of them within the promoter region and one in intron, were selected and genotyped with a polymerase chain reaction-ligase detection reaction (PCR-LDR) method. No association was revealed between these SNPs or the haplotypes containing four promoter SNPs and the risk of sAD. The results of this study indicate that polymorphisms in the selected regions of the NTRK2 gene are unlikely to confer the susceptibility of sAD in the Chinese Han population.


Assuntos
Doença de Alzheimer/genética , Grupo com Ancestrais do Continente Asiático/genética , Receptor trkB/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/etnologia , Estudos de Casos e Controles , China , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas
20.
Neuroreport ; 24(9): 464-8, 2013 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-23660633

RESUMO

Increasing evidence shows that sortilin (encoded by SORT1 gene), a member of the vacuolar protein sorting 10 family of sorting receptors, can modulate amyloid-ß peptides (Aß) metabolism and clearance, as well as mediate the neurotoxicity of the Aß oligomer and proneurotrophins, thus playing diverse roles in the pathogenesis of Alzheimer's disease. To assess the association between single nucleotide polymorphism (SNP) of the SORT1 gene and sporadic Alzheimer's disease (sAD) in the Chinese Han population, a case-control study was carried out including 220 sAD patients and 245 controls. One tag SNP was selected from the entire SORT1 gene through construction of linkage disequilibrium blocks, and three SNPs located in the vicinity of SORT1 that affect its expression were also selected. The four target SNPs were genotyped using a multiplex PCR-ligase detection reaction method, yielding no significant association between them or haplotypes containing three of them, and the risk of sAD. The results of this study indicate that polymorphisms of the SORT1 gene are unlikely to confer the risk of sAD in the Chinese Han population.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Doença de Alzheimer/etnologia , Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade
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