Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 25
Article in English | WPRIM | ID: wpr-922756


Physalin B (PB), one of the major active steroidal constituents of Solanaceae Physalis plants, has a wide variety of biological activities. We found that PB significantly down-regulated β-amyloid (Aβ) secretion in N2a/APPsw cells. However, the underlying mechanisms are not well understood. In the current study, we investigated the changes in key enzymes involved in β-amyloid precursor protein (APP) metabolism and other APP metabolites by treating N2a/APPsw cells with PB at different concentrations. The results indicated that PB reduced Aβ secretion, which was caused by down-regulation of β-secretase (BACE1) expression, as indicated at both the protein and mRNA levels. Further research revealed that PB regulated BACE1 expression by inducing the activation of forkhead box O1 (FoxO1) and inhibiting the phosphorylation of signal transducer and activator of transcription 3 (STAT3). In addition, the effect of PB on BACE1 expression and Aβ secretion was reversed by treatment with FoxO1 siRNA and STAT3 antagonist S3I-201. In conclusion, these data demonstrated that PB can effectively down-regulate the expression of BACE1 to reduce Aβsecretion by activating the expression of FoxO1 and inhibiting the phosphorylation of STAT3.

Alzheimer Disease , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Aspartic Acid Endopeptidases/metabolism , Down-Regulation , Forkhead Box Protein O1/genetics , Humans , Phosphorylation , STAT3 Transcription Factor/metabolism , Secosteroids
Acta Physiologica Sinica ; (6): 845-854, 2021.
Article in Chinese | WPRIM | ID: wpr-921288


The aim of the present study was to explore the correlation between ptk2b/PTK2B (protein tyrosine kinase 2 beta, a ptk2b-encoded protein) and the level of low density lipoprotein receptor-related protein-1 (LRP-1), as well as to uncover the relationship between the changes in beta amyloid protein (Aβ) levels in blood and brain and the expression of ptk2b in Aβ-induced cognitive dysfunction mice. A total of 64 3-month-old C57BL/6J mice were divided randomly into the experimental group and control group. All mice underwent the intracerebroventricular (i.c.v.) intubation. Mice in the experimental group received the i.c.v. infusion of oligomeric Aβ

Alzheimer Disease , Amyloid beta-Peptides/metabolism , Animals , Brain , Cognitive Dysfunction/chemically induced , Disease Models, Animal , Focal Adhesion Kinase 2 , Hippocampus/metabolism , Mice , Mice, Inbred C57BL , Peptide Fragments
Article in English | WPRIM | ID: wpr-879970


Transient receptor potential M2 (TRPM2) ion channel is a non-selective cationic channel that can permeate calcium ions, and plays an important role in neuroinflammation, ischemic reperfusion brain injury, neurodegenerative disease, neuropathic pain, epilepsy and other neurological diseases. In ischemic reperfusion brain injury, TRPM2 mediates neuronal death by modulating the different subunits of glutamate N-methyl-D-aspartic acid receptor in response to calcium/zinc signal. In Alzheimer's disease, TRPM2 is activated by reactive oxygen species generated by β-amyloid peptide to form a malignant positive feedback loop that induces neuronal death and is involved in the pathological process of glial cells by promoting inflammatory response and oxidative stress. In epilepsy, the TRPM2-knockout alleviates epilepsy induced neuronal degeneration by inhibiting autophagy and apoptosis related proteins. The roles of TRPM2 channel in the pathogenesis of various central nervous system diseases and its potential drug development and clinical application prospects are summarized in this review.

Amyloid beta-Peptides/metabolism , Humans , Neurodegenerative Diseases , Neuroglia , TRPM Cation Channels/genetics , Transient Receptor Potential Channels
Arq. neuropsiquiatr ; 78(5): 277-281, May 2020. tab, graf
Article in English | LILACS | ID: biblio-1131706


ABSTRACT Background: Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder caused by progressive deposition of β-amyloid peptides in the walls of small and medium-sized cortical and leptomeningeal vessels. Until today, the prevalence of CAA is unknown in our region. Objective: This study aims to analyze the prevalence of this entity in a specific elderly population in a tertiary hospital in Northeastern Brazil. Methods: A cross-sectional, retrospective study with the enrollment of patients aged 65 or older followed in the neurological outpatient service of the Universidade Federal do Piauí, Brazil, who underwent brain magnetic resonance imaging (MRI) from July 2016 to June 2018. Results: One hundred and seventy-four patients were enrolled, of whom 100 were women (57.4%) and 74, men (42.6%), aged from 65 to 91 years old (median age 73.27). Nine patients were excluded from the study due to unavailability of MRI sequences needed for an appropriate analysis. Out of the 165 remaining patients, 12 (7.2%) had established the diagnosis of CAA, according to the modified Boston criteria. Conclusion: The prevalence of CAA in our study was like those of medical literature, with a progressive age-related increase.

RESUMO Introdução: A angiopatia amiloide cerebral (AAC) é uma desordem vascular causada pela deposição progressiva de peptídeos β-amiloides nas paredes de pequenos e médios vasos corticais e leptomeníngeos. Até a presente data, a epidemiologia da AAC é desconhecida em nossa região. Objetivos: Avaliar a prevalência da AAC em uma população específica de pacientes idosos de um hospital terciário no nordeste brasileiro. Métodos: Estudo transversal, retrospectivo, com seleção de pacientes com idade igual ou superior a 65 anos, acompanhados no serviço de Neurologia do Hospital Universitário da Universidade Federal do Piauí, Brasil, e que foram submetidos a exame de ressonância nuclear magnética entre julho de 2016 e junho de 2018. Resultados: Foram recrutados 174 pacientes, dos quais 100 eram mulheres (57,4%) e 74 homens (42,6%), com idades entre 65 e 91 anos (média de 73,27). Nove pacientes foram excluídos devido à indisponibilidade de sequências de ressonância magnética necessárias para uma análise apropriada. Dos 165 pacientes restantes, 12 (7,2%) foram diagnosticados com AAC de acordo com os critérios de Boston modificados. Conclusão: A prevalência da AAC em nosso estudo foi semelhante ao resultado encontrado na literatura médica, com um aumento progressivo relacionado à idade.

Humans , Male , Female , Aged , Aged, 80 and over , Cerebral Amyloid Angiopathy , Brazil , Boston , Cross-Sectional Studies , Retrospective Studies , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/chemistry
Int. j. morphol ; 38(1): 230-234, Feb. 2020. graf
Article in English | LILACS | ID: biblio-1056427


The hypotheses currently considered the most likely causes of Alzheimer's disease (AD) are amyloid beta peptide deposition in the cerebral cortex and hyperphosphorylation of the Tau protein, with the consequent formation of neurofibrillary tangles. In clinical practice, although not accurate, AD diagnosis is based on the exclusion of other diseases, behavioural assessments and complementary examinations, such as imaging and blood tests. Advances in the field of biotechnology have created exciting prospects for the early detection of AD via biomarker assessment, which is considered a safer and more efficient procedure. Molecules recognised as biomarkers can be expressed in some body fluids, including cerebrospinal fluid, saliva and blood. The presence of amyloid beta peptide and Tau can be confirmed in saliva, which is also an easily and non-invasively collectable material with an accessible cost. The objective was evaluate the concentrations of the t-Tau protein and Ab42 peptide in the saliva of elderly individuals with and without dementia of the AD type Method: The objective of this case-control study, involving a total of 120 individuals, was to analyse whether a correlation exists between variations in the concentrations of the t-Tau and Ab42 biomarkers in the saliva of patients with confirmed AD and individuals in the inclusion group but without AD . We found that t-Tau expression in AD patients is significantly lower than that in individuals without AD, whereas the salivary concentration of Ab42 is higher in patients with AD but not significantly different from that of the group without AD. Conclusion: Thus, we demonstrate the feasibility of using salivary biomarkers as predictive markers for diagnosis of Alzheimer's disease.

Las hipótesis consideradas actualmente como las causas más probables de la enfermedad de Alzheimer (EA) son la deposición de péptido beta amiloide en la corteza cerebral y la hiperfosforilación de la proteína Tau, con la consiguiente formación de ovillos neurofibrilares. En la práctica clínica, aunque no es precisa, el diagnóstico de la EA se basa en la exclusión de otras enfermedades, evaluaciones de comportamiento y exámenes complementarios, como imágenes y análisis de sangre. Los avances en el campo de la biotecnología han creado interesantes perspectivas para la detección temprana de la EA a través de la evaluación de biomarcadores, que se considera un procedimiento más seguro y más eficiente. Las moléculas reconocidas como biomarcadores se pueden expresar en algunos fluidos corporales, incluidos el líquido cerebroespinal, la saliva y la sangre. La presencia del péptido beta amiloide (AB) y la proteína Tau (t-Tau) se puede confirmar en la saliva, que también es un material fácil y no invasivo de recolección con un costo accesible. El objetivo fue evaluar las concentraciones de la proteína t-Tau y el péptido Ab42 en la saliva de las personas de edad avanzada con y sin demencia del tipo de tipo EA. El estudio de casos y controles, se realizó en un total de 120 personas, para analizar si existe una correlación entre las variaciones en las concentraciones de los biomarcadores t-Tau y Ab42 en la saliva de pacientes con EA confirmada e individuos en el grupo de inclusión pero sin AD. Encontramos que la expresión de t-Tau en pacientes con EA es significativamente menor que en individuos sin EA, mientras que la concentración salival de Ab42 es mayor en pacientes con EA pero no significativamente diferente de la del grupo sin la enfermedad . Por lo tanto, se demuestra la viabilidad del uso de biomarcadores salivales como marcadores predictivos para el diagnóstico de la enfermedad de Alzheimer.

Humans , Male , Female , Middle Aged , Aged , Amyloid beta-Peptides/metabolism , tau Proteins/metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Saliva/metabolism , Saliva/chemistry , Biomarkers/analysis , Biomarkers/metabolism , Amyloid beta-Peptides/analysis , tau Proteins/analysis
Biol. Res ; 51: 35, 2018. graf
Article in English | LILACS | ID: biblio-983939


BACKGROUND: The previous studies have demonstrated the reduction of thiamine diphosphate is specific to Alzheimer's disease (AD) and causal factor of brain glucose hypometabolism, which is considered as a neurodegenerative index of AD and closely correlates with the degree of cognitive impairment. The reduction of thiamine diphosphate may contribute to the dysfunction of synapses and neural circuits, finally leading to cognitive decline. RESULTS: To demonstrate this hypothesis, we established abnormalities in the glucose metabolism utilizing thiamine deficiency in vitro and in vivo, and we found dramatically reduced dendrite spine density. We further detected lowered excitatory neurotransmission and impaired hippocampal long-term potentiation, which are induced by TPK RNAi in vitro. Importantly, via treatment with benfotiamine, Aß induced spines density decrease was considerably ameliorated. CONCLUSIONS: These results revealed that thiamine deficiency contributed to synaptic dysfunction which strongly related to AD pathogenesis. Our results provide new insights into pathogenesis of synaptic and neuronal dysfunction in AD.

Animals , Male , Synapses/physiology , Thiamine Deficiency/complications , Thiamine Deficiency/metabolism , Thiamine Pyrophosphate/deficiency , Alzheimer Disease/etiology , Alzheimer Disease/metabolism , Neurons/physiology , Thiamine Deficiency/physiopathology , Thiamine Pyrophosphate/metabolism , Random Allocation , Blotting, Western , Amyloid beta-Peptides/metabolism , Rats, Sprague-Dawley , Diphosphotransferases/metabolism , Synaptic Transmission/physiology , Dendritic Spines/metabolism , Alzheimer Disease/physiopathology , Real-Time Polymerase Chain Reaction , Glucose/metabolism , Hippocampus/physiopathology , Hippocampus/metabolism , Mice, Inbred C57BL
Rev. bras. neurol ; 53(4): 17-26, out.-dez. 2017. tab, graf
Article in Portuguese | LILACS | ID: biblio-876889


Fundamento: a Doença de Alzheimer (DA) é o tipo mais comum de demência, sendo histologicamente caracterizada pela deposição de peptídeo ß-amiloide, hiperfosforilação da proteína tau, neuroinflamação e perda neuronal, favorecida por diferentes mecanismos fisiopatológicos. O diabetes mellitus tipo 2 (DM2) ocorre devido à resistência periférica à insulina e à insuficiência insulínica (em fases mais avançadas da doença). Dados epidemiológicos sugerem relação entre DA e DM2, embora os supostos mecanismos fisiopatológicos comuns dessa inter-relação sejam obscuros. Objetivos: revisar os principais mecanismos fisiopatológicos compartilhados pela DA e DM2. Métodos: foram pesquisados artigos de 2000 a 2017 nas bases de dados do Portal CAPES/MEC, utilizando as palavras-chave: doença de Alzheimer, diabetes mellitus tipo 2, lesão vascular, resistência à insulina e estresse oxidativo. Resultados: 127 publicações foram analisadas e 73 incluídas. Lesão endotelial, resistência à insulina e estresse oxidativo foram os aspectos fisiopatológicos mais importantes e comuns à DA e DM2. Conclusão: há indícios de relação entre DA e DM2, embora não esteja clara se a relação é causal. Consequentemente, há a necessidade de estudos mais aprofundados sobre marcadores e mecanismos relacionados, visando o desenvolvimento de programas de prevenção e intervenção nas duas doenças em conjunto. (AU)

Introduction: Alzheimer's Disease (AD) is the most common type of dementia and is histologically characterized by deposition of ß-amyloid peptide, hyperphosphorylation of tau protein, neuronal loss and neuroinflammation, favored by different pathophysiological mechanisms. The type 2 diabetes mellitus (T2DM) occurs due to peripheral insulin resistance and insulin insufficiency (in later stages of the disease). Epidemiological data suggest a relationship between AD and T2DM, although the supposed common pathophysiological mechanisms of this interrelation are obscure. Objectives: to review the main pathophysiological mechanisms possibly shared by AD and T2DM. Methods: articles were searched from 2000 to 2017 in the databases of Portal CAPES / MEC, using the key words: Alzheimer's disease, type 2 diabetes mellitus, vascular injury, insulin resistance and oxidative stress. Results: we selected 73 from 127 articles. Endothelial injury, insulin resistance and oxidative stress are pathophysiological aspects common to AD and T2DM. Conclusion: there is evidence of a relationship between AD and T2DM, although it is unclear whether the relation is causal. There is a need for more studies about markers and related mechanisms, aiming at the development of prevention and intervention programs in both diseases. (AU)

Humans , Aged , Aged, 80 and over , Diabetes Mellitus, Type 2/epidemiology , Alzheimer Disease/complications , Alzheimer Disease/physiopathology , Alzheimer Disease/epidemiology , Insulin Resistance , Risk Factors , Amyloid beta-Peptides/metabolism , Oxidative Stress , Disease Progression
Arq. neuropsiquiatr ; 74(9): 737-744, Sept. 2016. graf
Article in English | LILACS | ID: lil-796045


ABSTRACT Cell physiology is impaired before protein aggregation and this may be more relevant than inclusions themselves for neurodegeneration. The present study aimed to characterize an animal model to enable the analysis of the cell biology before and after protein aggregation. Ten-month-old Lewis rats were exposed either to 1 or 2 mg/kg/day of rotenone, delivered subcutaneously through mini-pumps, for one month. Hyperphosphorylated TAU, alpha-synuclein, amyloid-beta peptide and protein carbonylation (indicative of oxidative stress) were evaluated in the hippocampus, substantia nigra and locus coeruleus through immunohistochemistry or western blot. It was found that 2 mg/kg/day rotenone increased amyloid-beta peptide, hyperphosphorylation of TAU and alpha-synuclein. Rotenone at 1mg/kg/day did not alter protein levels. Protein carbonylation remained unchanged. This study demonstrated that aged Lewis rats exposed to a low dose of rotenone is a useful model to study cellular processes before protein aggregation, while the higher dose makes a good model to study the effects of protein inclusions.

RESUMO A fisiologia celular está prejudicada antes da agregação proteica podendo ser mais importante para a neurodegeneração do que as próprias inclusões. Assim, o objetivo deste estudo é caracterizar um modelo animal para analisar os mecanismos e efeitos da agregação proteica. Ratos Lewis com 10 meses de idade foram expostos a rotenona (1 ou 2 mg/kg/dia), administrada subcutaneamente, utilizando minibombas osmóticas. Os níveis de peptídeo beta-amiloide, TAU hiperfosforilada, alfa-sinucleína e proteínas carboniladas (indicativo de estresse oxidativo) foram avaliados por imunohistoquímica e western blot no hipocampo, substância negra e locus coeruleus. Foi demonstrado que 2 mg/kg/dia de rotenona promoveu aumento do peptídeo beta-amiloide, hiperfosforilação da TAU e alfa-sinucleína. Já 1 mg/kg/dia de rotenona não alterou os níveis dessas proteína nessas regiões. As proteínas carboniladas não se alteraram. Foi demonstrado que ratos Lewis idosos expostos a baixas doses de rotenona são modelo de estudo dos processos celulares antes da agregação proteica, enquanto 2 mg/kg/dia de rotenona permite estudos sobre os efeitos da agregação proteica.

Animals , Male , Rotenone/administration & dosage , Central Nervous System/drug effects , Central Nervous System/pathology , Disease Models, Animal , Protein Aggregation, Pathological/chemically induced , Protein Aggregation, Pathological/pathology , Rats, Inbred Lew , Substantia Nigra/drug effects , Immunohistochemistry , Central Nervous System/metabolism , Blotting, Western , Reproducibility of Results , Amyloid beta-Peptides/drug effects , Amyloid beta-Peptides/metabolism , Oxidative Stress , alpha-Synuclein/drug effects , alpha-Synuclein/metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/pathology
Article in English | WPRIM | ID: wpr-225578


This study aimed to investigate the independent and interactive influences of apolipoprotein E (APOE) epsilon4 and beta-amyloid (Abeta) on multiple cognitive domains in a large group of cognitively normal (CN) individuals and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Participants were included if clinical and cognitive assessments, amyloid imaging, and APOE genotype were all available from the Alzheimer's Disease Neuroimaging Initiative database (CN = 324, MCI = 502, AD = 182). Individuals with one or two copies of epsilon4 were designated as APOE epsilon4 carriers (epsilon4+); individuals with no epsilon4 were designated as APOE epsilon4 non-carriers (epsilon4-). Based on mean florbetapir standard uptake value ratios, participants were classified as Abeta burden-positive (Abeta+) or Abeta burden-negative (Abeta-). In MCI, APOE epsilon4 effects were predominantly observed on frontal executive function, with epsilon4+ participants exhibiting poorer performances; Abeta positivity had no influence on this effect. Abeta effects were observed on global cognition, memory, and visuospatial ability, with Abeta+ participants exhibiting poorer performances. Measures of frontal executive function were not influenced by Abeta. Interactive effects of APOE epsilon4+ and Abeta were observed on global cognition and verbal recognition memory. Abeta, not APOE epsilon4+, influenced clinical severity and functional status. The influences of APOE epsilon4+ and Abeta on cognitive function were minimal in CN and AD. In conclusion, we provide further evidence of both independent and interactive influences of APOE epsilon4+ and Abeta on cognitive function in MCI, with APOE epsilon4+ and Abeta showing dissociable effects on executive and non-executive functions, respectively.

Aged , Aged, 80 and over , Alzheimer Disease/genetics , Amyloid beta-Peptides/metabolism , Aniline Compounds/chemistry , Apolipoprotein E4/genetics , Brain/diagnostic imaging , Cognition , Databases, Factual , Demography , Ethylene Glycols/chemistry , Female , Genotype , Humans , Male , Cognitive Dysfunction/genetics , Positron-Emission Tomography
Mem. Inst. Oswaldo Cruz ; 110(1): 86-94, 03/02/2015. tab, graf
Article in English | LILACS | ID: lil-741617


Trypanosoma cruzi strains from distinct geographic areas show differences in drug resistance and association between parasites genetic and treatment response has been observed. Considering that benznidazole (BZ) can reduce the parasite burden and tissues damage, even in not cured animals and individuals, the goal is to assess the drug response to BZ of T. cruzi II strains isolated from children of the Jequitinhonha Valley, state of Minas Gerais, Brazil, before treatment. Mice infected and treated with BZ in both phases of infection were compared with the untreated and evaluated by fresh blood examination, haemoculture, polymerase chain reaction, conventional (ELISA) and non-conventional (FC-ALTA) serologies. In mice treated in the acute phase, a significant decrease in parasitaemia was observed for all strains. Positive parasitological and/or serological tests in animals treated during the acute and chronic (95.1-100%) phases showed that most of the strains were BZ resistant. However, beneficial effect was demonstrated because significant reduction (p < 0.05%) and/or suppression of parasitaemia was observed in mice infected with all strains (acute phase), associated to reduction/elimination of inflammation and fibrosis for two/eight strains. BZ offered some benefit, even in not cured animals, what suggest that BZ use may be recommended at least for recent chronic infection of the studied region.

Humans , Drug Discovery , Industrial Waste/analysis , Nootropic Agents/isolation & purification , Plant Extracts/chemistry , Plant Shoots/chemistry , Stilbenes/isolation & purification , Vitis/chemistry , Agriculture/economics , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Benzofurans/analysis , Benzofurans/chemistry , Benzofurans/economics , Benzofurans/isolation & purification , Chromatography, High Pressure Liquid , France , Industrial Waste/economics , Molecular Structure , Neuroprotective Agents/chemistry , Neuroprotective Agents/economics , Neuroprotective Agents/isolation & purification , Neuroprotective Agents/pharmacology , Nootropic Agents/chemistry , Nootropic Agents/economics , Nootropic Agents/pharmacology , Protein Aggregation, Pathological , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Phenols/chemistry , Phenols/economics , Plant Extracts/economics , Protein Aggregates/drug effects , Spectrometry, Mass, Electrospray Ionization , Stereoisomerism , Stilbenes/analysis , Stilbenes/chemistry , Stilbenes/economics , Stilbenes/pharmacology
Article in English | WPRIM | ID: wpr-57309


Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that includes obesity, diabetes, and dyslipidemia. Accumulating evidence implies that MetS contributes to the development and progression of Alzheimer's disease (AD); however, the factors connecting this association have not been determined. Insulin resistance (IR) is at the core of MetS and likely represent the key link between MetS and AD. In the central nervous system, insulin plays key roles in learning and memory, and AD patients exhibit impaired insulin signaling that is similar to that observed in MetS. As we face an alarming increase in obesity and T2D in all age groups, understanding the relationship between MetS and AD is vital for the identification of potential therapeutic targets. Recently, several diabetes therapies that enhance insulin signaling are being tested for a potential therapeutic benefit in AD and dementia. In this review, we will discuss MetS as a risk factor for AD, focusing on IR and the recent progress and future directions of insulin-based therapies.

Alzheimer Disease/etiology , Amyloid beta-Peptides/metabolism , Animals , Brain/metabolism , Cognition Disorders/etiology , Humans , Insulin/metabolism , Insulin Resistance , Metabolic Syndrome/complications , Molecular Targeted Therapy , Signal Transduction/drug effects , tau Proteins/metabolism
Article in English | WPRIM | ID: wpr-57308


Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into beta-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons.

Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Amyotrophic Lateral Sclerosis/drug therapy , Animals , Autophagy/drug effects , DNA-Binding Proteins/metabolism , Humans , Huntington Disease/drug therapy , Lysosomes/metabolism , Molecular Targeted Therapy , Mutation , Nerve Tissue Proteins/genetics , Neurodegenerative Diseases/drug therapy , Parkinson Disease/drug therapy , PrPSc Proteins/metabolism , Prion Diseases/drug therapy , Proteasome Endopeptidase Complex/metabolism , Proteolysis , Proteostasis Deficiencies/metabolism , Superoxide Dismutase/metabolism , Ubiquitin/metabolism , alpha-Synuclein/metabolism , tau Proteins/metabolism
Indian J Biochem Biophys ; 2014 Aug; 51(4): 257-262
Article in English | IMSEAR | ID: sea-154241


Obesity arising due to the dietary and life style changes is fast reaching epidemic proportions all over the world. There is increasing evidence that the incidence of Alzheimer disease (AD) is significantly influenced by a cluster of metabolic diseases, including diabetes and obesity. This study was aimed to test the suitability of experimentally-induced obesity in rats as an experimental animal model of AD. We used the procedure of neonatal administration of rats with monosodium L-glutamate (MSG), which generates adult obese animals as our study design and assessed the AD-like changes by measuring amyloid ß (1-42) and acetylcholinesterase (AChE) levels in the hippocampal extracts and cognitive impairments by Barnes maze task. Further, we investigated the influence of anti-obesity substance [D-Lys (3)] GHRP-6 on blood glucose, hippocampal Aß, AChE levels and restoration of cognitive deficits. Results revealed that administration of MSG to neonatal rats exhibited increased body mass index and serum glucose levels over the controls. Measurement of markers for AD-like molecular changes i.e. amyloid ß (Aß) and AChE levels showed marked elevation in these two parameters in the hippocampus of MSG-treated rats. Assessment of cognitive abilities by Barnes maze revealed spatial disorientation characteristic of AD. Administration of ghrelin receptor analog [D-Lys (3)] GHRP-6 to obese rats resulted in significant restoration of serum cholesterol, glucose, leptin and ghrelin levels to that of control with concomitant reduction in hippocampal Aß and AChE levels. In addition, the treated animals exhibited marked improvement in Barne’s maze task. These findings suggest that MSG-induced obese rats may serve as non-transgenic animal model for AD research. Further, the results indicate the potential of [D-Lys (3)] GHRP-6 as a promising anti-Alzheimer candidate.

Amyloid beta-Peptides/metabolism , Animals , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Male , Obesity/metabolism , Oligopeptides/physiology , Rats , Rats, Sprague-Dawley
Article in English | WPRIM | ID: wpr-72394


The receptor for advanced glycation end products (RAGE) has been reported to have a pivotal role in the pathogenesis of Alzheimer's disease (AD). This study investigated RAGE levels in the hippocampus and cortex of a triple transgenic mouse model of AD (3xTg-AD) using western blotting and immunohistochemical double-labeling to assess cellular localization. Analysis of western blots showed that there were no differences in the hippocampal and cortical RAGE levels in 10-month-old adult 3xTg-AD mice, but significant increases in RAGE expression were found in the 22- to 24-month-old aged 3xTg-AD mice compared with those of age-matched controls. RAGE-positive immunoreactivity was observed primarily in neurons of aged 3xTg-AD mice with very little labeling in non-neuronal cells, with the notable exception of RAGE presence in astrocytes in the hippocampal area CA1. In addition, RAGE signals were co-localized with the intracellular amyloid precursor protein (APP)/amyloid beta (Abeta) but not with the extracellular APP/Abeta. In aged 3xTg-AD mice, expression of human tau was observed in the hippocampal area CA1 and co-localized with RAGE signals. The increased presence of RAGE in the 3xTg-AD animal model showing critical aspects of AD neuropathology indicates that RAGE may contribute to cellular dysfunction in the AD brain.

Receptor for Advanced Glycation End Products , Alzheimer Disease/genetics , Amyloid beta-Peptides/metabolism , Animals , Astrocytes/metabolism , CA1 Region, Hippocampal/growth & development , Humans , Mice , Mice, Transgenic , Neurons/metabolism , Receptors, Immunologic/genetics , tau Proteins/genetics
Braz. j. med. biol. res ; 46(8): 659-669, ago. 2013. graf
Article in English | LILACS | ID: lil-684523


Chronic inflammation induced by amyloid-beta (Aβ) plays a key role in the development of age-related macular degeneration (AMD), and matrix metalloproteinase-9 (MMP-9), interleukin (IL)-6, and IL-8 may be associated with chronic inflammation in AMD. Sirtuin 1 (SIRT1) regulates inflammation via inhibition of nuclear factor-kappa B (NF-κB) signaling, and resveratrol has been reported to prevent Aβ-induced retinal degeneration; therefore, we investigated whether this action was mediated via activation of SIRT1 signaling. Human adult retinal pigment epithelial (RPE) cells were exposed to Aβ, and overactivation and knockdown of SIRT1 were performed to investigate whether SIRT1 is required for abrogating Aβ-induced inflammation. We found that Aβ-induced RPE barrier disruption and expression of IL-6, IL-8, and MMP-9 were abrogated by the SIRT1 activator SRT1720, whereas alterations induced by Aβ in SIRT1-silenced RPE cells were not attenuated by SRT1720. In addition, SRT1720 inhibited Aβ-mediated NF-κB activation and decrease of the NF-κB inhibitor, IκBα. Our findings suggest a protective role for SIRT1 signaling in Aβ-dependent retinal degeneration and inflammation in AMD.

Adult , Humans , Amyloid beta-Peptides/metabolism , Inflammation/chemically induced , Macular Degeneration/prevention & control , NF-kappa B/metabolism , Retinal Pigment Epithelium/drug effects , Signal Transduction/physiology , Sirtuin 1/physiology , Antioxidants/pharmacology , Blood-Retinal Barrier/physiopathology , Cell Survival/drug effects , Enzyme Assays/methods , Gene Silencing , /pharmacology , /metabolism , /metabolism , Macular Degeneration/chemically induced , Macular Degeneration/physiopathology , Matrix Metalloproteinase 9/metabolism , NF-kappa B/drug effects , Primary Cell Culture , Real-Time Polymerase Chain Reaction , RNA Interference , Retinal Pigment Epithelium/metabolism , Stilbenes/pharmacology
Article in English | WPRIM | ID: wpr-35839


Cellular prion protein, a membrane protein, is expressed in all mammals. Prion protein is also found in human blood as an anchorless protein, and this protein form is one of the many potential sources of misfolded prion protein replication during transmission. Many studies have suggested that beta-amyloid1-42 oligomer causes neurotoxicity associated with Alzheimer's disease, which is mediated by the prion protein that acts as a receptor and regulates the hippocampal potentiation. The prevention of the binding of these proteins has been proposed as a possible preventative treatment for Alzheimer's disease; therefore, a greater understanding of the binding hot-spots between the two molecules is necessary. In this study, the epitope mapping immunoassay was employed to characterize binding epitopes within the prion protein and complementary epitopes in beta-amyloid. Residues 23-39 and 93-119 in the prion protein were involved in binding to beta-amyloid1-40 and 1-42, and monomers of this protein interacted with prion protein residues 93-113 and 123-166. Furthermore, beta-amyloid antibodies against the C-terminus detected bound beta-amyloid1-42 at residues 23-40, 104-122 and 159-175. beta-Amyloid epitopes necessary for the interaction with prion protein were not determined. In conclusion, charged clusters and hydrophobic regions of the prion protein were involved in binding to beta-amyloid1-40 and 1-42. The 3D structure appears to be necessary for beta-amyloid to interact with prion protein. In the future, these binding sites may be utilized for 3D structure modeling, as well as for the pharmaceutical intervention of Alzheimer's disease.

Amyloid beta-Peptides/metabolism , Electrophoresis , Enzyme-Linked Immunosorbent Assay , Epitope Mapping , Epitopes/metabolism , Humans , Immunoassay , Prions/metabolism , Protein Binding , Recombinant Proteins/metabolism
Article in English | WPRIM | ID: wpr-110118


The plant viral protease, NIa, has a strict substrate specificity for the consensus sequence of Val-Xaa-His-Gln, with a scissoring property after Gln. We recently reported that NIa efficiently cleaved the amyloid-beta (Abeta) peptide, which contains the sequence Val-His-His-Gln in the vicinity of the cleavage site by alpha-secretase, and that the expression of NIa using a lentiviral system in the brain of AD mouse model reduced plaque deposition levels. In the present study, we investigated whether exogenous expression of NIa in the brain of AD mouse model is beneficial to the improvement of cognitive deficits. To address this question, Lenti-NIa was intracerebrally injected into the brain of Tg-APPswe/PS1dE9 (Tg-APP/PS1) mice at 7 months of age and behavioral tests were performed 15-30 days afterwards. The results of the water maze test indicated that Tg-APP/PS1 mice which had been injected with Lenti-GFP showed an increased latency in finding the hidden-platform and markedly enhanced navigation near the maze-wall, and that such behavioral deficits were significantly reversed in Tg-APP/PS1 mice injected with Lenti-NIa. In the passive avoidance test, Tg-APP/PS1 mice exhibited a severe deficit in their contextual memory retention, which was reversed by NIa expression. In the marble burying test, Tg-APP/PS1 mice buried marbles fewer than non-transgenic mice, which was also significantly improved by NIa. After behavioral tests, it was verified that the Tg-APP/PS1 mice with Lenti-NIa injection had reduced Abeta levels and plaque deposition when compared to Tg-APP/PS1 mice. These results showed that the plant viral protease, NIa, not only reduces Abeta pathology, but also improves behavioral deficits.

Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Animals , Avoidance Learning , Brain/metabolism , Cognition , Cognition Disorders , Disease Models, Animal , Endopeptidases/genetics , Gene Expression , Maze Learning , Memory , Mice , Mice, Inbred C57BL , Mice, Transgenic , Plaque, Amyloid/metabolism , Presenilin-1/genetics , Viral Proteins/genetics
Rev. méd. Chile ; 137(2): 289-295, feb. 2009.
Article in Spanish | LILACS | ID: lil-516097


The pharmacological interventions for Alzheimer disease should be based in its pathogenic mechanisms such as amyloidogenesis, tau hyperphosphorilation, disturbances in neurotransmission and changes in neuronal trophism. Other therapies derive from epidemiological observations, such as antioxidants and anti-inflammatory drugs, estrogens, statins and anti hypertensive drugs. Some life style interventions, such as changes in diet, exercise and brain stimulation could also be beneficial for the prevention of Alzheimer disease. Ongoing research on pathogenic mechanisms promises the discovery of more effective therapies. Healthy life style should always be recommended due to its benefit and lack of untoward effects.

Animals , Humans , Alzheimer Disease/therapy , Life Style , Amyloid beta-Peptides/metabolism , Amyloidosis/drug therapy , Amyloidosis/prevention & control , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antihypertensive Agents/therapeutic use , Diet , Disease Models, Animal , Exercise , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
Rev. chil. nutr ; 35(supl.1): 250-260, nov. 2008. ilus
Article in Spanish | LILACS | ID: lil-523024


Alzheimer's disease (AD) is a major public health problem in many countries of the world; however the specific cause of this disease is still unknown. Currently, a bulk of evidence supports the hypothesis that beta-amiloidpeptide could be the cause of synaptic injuries and neuronal death observed at the initial stages of the disease. Patients with AD show lower levels of docosahexaenoic acid (DHA, C22:6; omega-3) in plasma and brain tissue, as compared with age-matched controls. In addition, epidemiological studies indicate that a high intake of DHA may have protective properties against neurodegenerative diseases. These observations are supported by in vivo studies showing that diets rich in DHA reduce synaptic injuries and cognitive defects induced by the beta-amyloid peptide. Although the molecular basis of these neuroprotective effects are still unknown, a number of mechanisms have been proposed to explain this protection, such as: regulation in the expression of potentially protective genes, activation of anti-inflammatory pathways, and modulation of the functional properties of neuronal membranes along with changes in their structural characteristics and physical-chemical properties. The present work reviews and discusses the molecular basis of the hypothesis on the protective role of DHA in the prevention of AD.

La enfermedad de Alzheimer (EA) constituye un importante problema de salud pública en muchos países del mundo, sin embargo la causa específica de esta enfermedad todavía es desconocida. Actualmente, numerosas evidencias apoyan la hipótesis que modificaciones del péptido beta-amiloide podrían ser la causa más próxima de las lesiones sinápticas y muerte neuronal que ocurren en las etapas iniciales de la enfermedad. Los pacientes con EA muestran niveles más bajos de ácido docosahexaenoico (DHA, C22: 6; omega-3) en plasma y tejido cerebral, en comparación con controles pareados por edad. Además, los estudios epidemiológicos indican que una alta ingesta de DHA podría tener propiedades protectoras contraías enfermedades neurodegenerativas. Estas observaciones se sustentan por estudios in vivo que demuestran que las dietas ricas en DHA, limitan las lesiones sinápticas y disminuyen los defectos cognitivos inducidos por el péptido beta-amiloide. Aunque las bases moleculares de estos efectos neuroprotectores aún siguen siendo desconocidas, se han propuesto varios mecanismos, tales como: la regulación de la expresión de genes potencialmente protectores, la activación de vías antiinflamatorias, la modulación de las propiedades funcionales de las membranas neuronales, junto con cambios en las características estructurales y físico-químicas de las mismas. Este trabajo revisa y discute el fundamento molecular de estas hipótesis sobre el rol del DHA en la protección de la EA.

Humans , Diet , Docosahexaenoic Acids , Alzheimer Disease/prevention & control , Docosahexaenoic Acids , Alzheimer Disease/metabolism , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/prevention & control , Inflammation , Oxidative Stress , Amyloid beta-Peptides/metabolism , Central Nervous System/metabolism
Gac. méd. Méx ; 142(3): 229-238, mayo-jun. 2006. ilus
Article in Spanish | LILACS | ID: lil-569680


La enfermedad de Alzheimer es la causa más común de demencia en la población de edad avanzada. Una de las características histopatológicas de esta enfermedad es la formación de placas seniles, cuyo componente proteínico es el péptido β-amiloide (Aβ) en su forma insoluble. Este péptido se produce normalmente en forma monomérica soluble y circula en concentraciones bajas en el líquido cefalorraquídeo y sangre. En concentraciones fisiológicas actúa como factor neurotrófico y neuroprotector, sin embargo con el envejecimiento y sobre todo en la enfermedad de Alzheimer se acumula, forma fibrillas insolubles y causa neurotoxicidad. La toxicidad del Aβ se ha asociado a la generación de radicales libres que causan peroxidación de lípidos y oxidación de proteínas entre otros daños. Se ha planteado que el Aβ pueda reconocer a receptores específicos que median a su vez neurotoxicidad. Entre estos se encuentra el receptor scavenger o pepenador que se expresa en la microglia y es capaz de internalizar agregados de este péptido. Independientemente de la vía de entrada del péptido a la célula, éste genera un estado de estrés oxidativo que eventualmente desencadena la muerte celular. Estudios recientes desarrollados en nuestro laboratorio muestran que el proceso de traducción de proteínas que intervienen en el proceso de endocitosis mediada por un receptor puede ser afectado por una condición de estrés oxidativo. Este es el caso de la β-adaptina, proteína clave en la formación del pozo cubierto.

Alzheimer's disease, the leading cause of dementia in the elderly is characterized by the presence in the brain of senile plaques formed of insoluble fibrillar deposits of beta-amyloid peptide. This peptide is normally produced in a monomeric soluble form and it is present in low concentrations in the blood and spinal fluid. At physiological concentrations, this peptide is a neurotrophic and neuroprotector factor; nevertheless, with aging and particularly in Alzheimer's disease this peptide accumulates, favors the formation of insoluble fibrils and causes neurotoxicity. beta-Amyloid peptide toxicity has been associated with the generation of free radicals that in turn promote lipid peroxidation and protein oxidation. Through the recognition of specific receptors such as the scavenger receptor, the beta-amyloid peptide becomes internalized in the form of aggregates. Independently of the way the peptide enters the cell, it generates oxidative stress that eventually triggers a state of neurotoxicity and cell death. Recent studies in our laboratory have shown the effect caused by an extracellular oxidative stress upon the internalization of the scavenger receptor. We have also demonstrated that the process of protein translation of molecules implicated in the mechanism of endocytosis through the scavenger receptor, such as the case of beta-adaptin, is arrested in microglial cells treated with beta-amyloid.

Humans , Alzheimer Disease/metabolism , Peptide Fragments/metabolism , Oxidative Stress , Amyloid beta-Peptides/metabolism