RESUMO
Heart failure (HF) is a major public health issue affecting more than 26 million people worldwide. HF is the most common cardiovascular disease in elder population; and it is associated with neurocognitive function decline, which represent underlying brain pathology diminishing learning and memory faculties. Both HF and neurocognitive impairment are associated with recurrent hospitalization episodes and increased mortality rate in older people, but particularly when they occur simultaneously. Overall, the published studies seem to confirm that HF patients display functional impairments relating to attention, memory, concentration, learning, and executive functioning compared with age-matched controls. However, little is known about the molecular mechanisms underpinning neurocognitive decline in HF. The present review round step recent evidence related to the possible molecular mechanism involved in the establishment of neurocognitive disorders during HF. We will make a special focus on cerebral ischemia, neuroinflammation and oxidative stress, Wnt signaling, and mitochondrial DNA alterations as possible mechanisms associated with cognitive decline in HF. Also, we provide an integrative mechanism linking pathophysiological hallmarks of altered cardiorespiratory control and the development of cognitive dysfunction in HF patients. Graphical Abstract Main molecular mechanisms involved in the establishment of cognitive impairment during heart failure. Heart failure is characterized by chronic activation of brain areas responsible for increasing cardiac sympathetic load. In addition, HF patients also show neurocognitive impairment, suggesting that the overall mechanisms that underpin cardiac sympathoexcitation may be related to the development of cognitive disorders in HF. In low cardiac output, HF cerebral infarction due to cardiac mural emboli and cerebral ischemia due to chronic or intermittent cerebral hypoperfusion has been described as a major mechanism related to the development of CI. In addition, while acute norepinephrine (NE) release may be relevant to induce neural plasticity in the hippocampus, chronic or tonic release of NE may exert the opposite effects due to desensitization of the adrenergic signaling pathway due to receptor internalization. Enhanced chemoreflex drive is a major source of sympathoexcitation in HF, and this phenomenon elevates brain ROS levels and induces neuroinflammation through breathing instability. Importantly, both oxidative stress and neuroinflammation can induce mitochondrial dysfunction and vice versa. Then, this ROS inflammatory pathway may propagate within the brain and potentially contribute to the development of cognitive impairment in HF through the activation/inhibition of key molecular pathways involved in neurocognitive decline such as the Wnt signaling pathway.
Assuntos
Insuficiência Cardíaca/psicologia , Deficiências da Aprendizagem/psicologia , Transtornos da Memória/psicologia , Transtornos Neurocognitivos/psicologia , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/metabolismo , Humanos , Deficiências da Aprendizagem/epidemiologia , Deficiências da Aprendizagem/metabolismo , Transtornos da Memória/epidemiologia , Transtornos da Memória/metabolismo , Transtornos Neurocognitivos/epidemiologia , Transtornos Neurocognitivos/metabolismo , Testes NeuropsicológicosRESUMO
Sporadic-inclusion body myositis (s-IBM) is the most common skeletal muscle disorder to afflict the elderly, and is clinically characterized by skeletal muscle degeneration. Its progressive course leads to muscle weakness and wasting, resulting in severe disability. The exact pathogenesis of this disease is unknown and no effective treatment has yet been found. An intriguing aspect of s-IBM is that it shares several molecular abnormalities with Alzheimer's disease, including the accumulation of amyloid-ß-peptide (Aß). Both disorders affect homeostasis of the cytotoxic fragment Aß(1-42) during aging, but they are clinically distinct diseases. The use of animals that mimic some characteristics of a disease has become important in the search to elucidate the molecular mechanisms underlying the pathogenesis. With the aim of analyzing Aß-induced pathology and evaluating the consequences of modulating Aß aggregation, we used Caenorhabditis elegans that express the Aß human peptide in muscle cells as a model of s-IBM. Previous studies indicate that copper treatment increases the number and size of amyloid deposits in muscle cells, and is able to ameliorate the motility impairments in Aß transgenic C. elegans. Our recent studies show that neuromuscular synaptic transmission is defective in animals that express the Aß-peptide and suggest a specific defect at the nicotine acetylcholine receptors level. Biochemical analyses show that copper treatment increases the number of amyloid deposits but decreases Aß-oligomers. Copper treatment improves motility, synaptic structure and function. Our results suggest that Aß-oligomers are the toxic Aß species that trigger neuromuscular junction dysfunction.
Assuntos
Cobre/uso terapêutico , Miosite de Corpos de Inclusão/tratamento farmacológico , Junção Neuromuscular/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans , HumanosRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-ß peptide (Aß) accumulation and synaptic alterations. Previous studies indicated that hyperforin, a component of the St John's Wort, prevents Aß neurotoxicity and some behavioral impairments in a rat model of AD. In this study we examined the ability of tetrahydrohyperforin (IDN5607), a stable hyperforin derivative, to prevent the cognitive deficit and synaptic impairment in an in vivo model of AD. In double transgenic APPswe/PSEN1ΔE9 mice, IDN5706 improves memory and prevents the impairment of synaptic plasticity in a dose-dependent manner, inducing a recovery of long-term potentiation. In agreement with these findings, IDN5706 prevented the decrease in synaptic proteins in hippocampus and cortex. In addition, decreased levels of tau hyperphosphorylation, astrogliosis, and total fibrillar and oligomeric forms of Aß were determined in double transgenic mice treated with IDN5706. In cultured cells, IDN5706 decreased the proteolytic processing of the amyloid precursor protein that leads to Aß peptide generation. These findings indicate that IDN5706 ameliorates AD neuropathology and could be considered of therapeutic relevance in AD treatment.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Floroglucinol/análogos & derivados , Presenilina-1/genética , Processamento de Proteína Pós-Traducional , Transmissão Sináptica/genética , Terpenos/farmacologia , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Floroglucinol/administração & dosagem , Floroglucinol/farmacologia , Processamento de Proteína Pós-Traducional/genética , Transmissão Sináptica/efeitos dos fármacos , Terpenos/administração & dosagemRESUMO
St. John's Wort (SJW) has been used medicinally for over 5,000 years. Relatively recently, one of its phloroglucinol derivatives, hyperforin, has emerged as a compound of interest. Hyperforin first gained attention as the constituent of SJW responsible for its antidepressant effects. Since then, several of its neurobiological effects have been described, including neurotransmitter re-uptake inhibition, the ability to increase intracellular sodium and calcium levels, canonical transient receptor potential 6 (TRPC6) activation, N-methyl-D-aspartic acid (NMDA) receptor antagonism as well as antioxidant and anti-inflammatory properties. Until recently, its pharmacological actions outside of depression had not been investigated. However, hyperforin has been shown to have cognitive enhancing and memory facilitating properties. Importantly, it has been shown to have neuroprotective effects against Alzheimer's disease (AD) neuropathology, including the ability to disassemble amyloid-beta (Abeta) aggregates in vitro, decrease astrogliosis and microglia activation, as well as improve spatial memory in vivo. This review will examine some of the early studies involving hyperforin and its effects in the central nervous system (CNS), with an emphasis on its potential use in AD therapy. With further investigation, hyperforin could emerge to be a likely therapeutical candidate in the treatment of this disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Antidepressivos/uso terapêutico , Floroglucinol/análogos & derivados , Terpenos/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Animais , Compostos Bicíclicos com Pontes/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Hypericum/química , Camundongos , Camundongos Transgênicos , Fármacos Neuroprotetores/uso terapêutico , Floroglucinol/uso terapêutico , Receptores de N-Metil-D-Aspartato/metabolismo , Canais de Cátion TRPC/metabolismo , Canal de Cátion TRPC6RESUMO
The major protein constituent of amyloid deposits in Alzheimer's disease (AD) is the amyloid beta-peptide (Abeta). In the present work, we have determined the effect of hyperforin an acylphloroglucinol compound isolated from Hypericum perforatum (St John's Wort), on Abeta-induced spatial memory impairments and on Abeta neurotoxicity. We report here that hyperforin: (1) decreases amyloid deposit formation in rats injected with amyloid fibrils in the hippocampus; (2) decreases the neuropathological changes and behavioral impairments in a rat model of amyloidosis; (3) prevents Abeta-induced neurotoxicity in hippocampal neurons both from amyloid fibrils and Abeta oligomers, avoiding the increase in reactive oxidative species associated with amyloid toxicity. Both effects could be explained by the capacity of hyperforin to disaggregate amyloid deposits in a dose and time-dependent manner and to decrease Abeta aggregation and amyloid formation. Altogether these evidences suggest that hyperforin may be useful to decrease amyloid burden and toxicity in AD patients, and may be a putative therapeutic agent to fight the disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/efeitos dos fármacos , Hypericum , Floroglucinol/análogos & derivados , Extratos Vegetais/farmacologia , Terpenos/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Amiloidose/tratamento farmacológico , Amiloidose/metabolismo , Análise de Variância , Animais , Compostos Bicíclicos com Pontes/farmacologia , Compostos Bicíclicos com Pontes/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Reação de Fuga/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Microinjeções , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Floroglucinol/farmacologia , Floroglucinol/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Terpenos/uso terapêutico , Fatores de TempoRESUMO
The nervous system of flatworms is quite simple although there is increasing evidence indicating that it is chemically complex. Studies of the nervous system in these animals have only been performed in the larval stage or in the adult worms, which are easy to obtain in nature, while the description of the nervous system in developing stages of these organisms is missing. Mesocestoides corti is a parasitic platyhelminth whose larvae can be induced in vitro to develop to adult, sexually mature worms, opening the possibility of studying the nervous system of a flatworm in different stages of development. Here, we describe the presence, activity, location, and molecular forms of acetylcholinesterase (AChE) in different stages of development of M. corti, from the larvae to adult forms of this endoparasite, obtained in in vitro cultures after induction of the larval stage with trypsin. Our results point to AChE as a molecular marker of the nervous system in platyhelminthes. The change in molecular forms of this enzyme and the increase in its activity during development from larvae to adult worm may reflect the presence of a more complex nervous system, necessary to adjust and coordinate the movement of a much bigger structure. A relationship between the development of the reproductive apparatus in segmented and adult worms with a more complex nervous system in these stages is also apparent. Finally, our study opens the possibility of applying anti-AChE as more effective therapeutic strategies against cestode parasites.
Assuntos
Acetilcolinesterase/metabolismo , Estágios do Ciclo de Vida/fisiologia , Mesocestoides/crescimento & desenvolvimento , Mesocestoides/metabolismo , Acetilcolinesterase/química , Animais , Feminino , Estágios do Ciclo de Vida/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Tripsina/farmacologiaRESUMO
Current evidence supports the notion that beta-amyloid deposits or Abeta intermediates may be responsible for the pathogenesis in Alzheimer's disease (AD) patients. In the present work, we have assessed the neuroprotective effect of the chronic intraperitoneal administration of a five-amino-acid beta-sheet breaker peptide (iAbeta5p) on the rat behavioral deficit induced by the intrahippocampal Abeta-fibrils injection. At 1 month after the injection, animals showed a partial reduction of the amyloid deposits formed and a decreased astrocytic response around the injection site. More importantly, we report that following the iAbeta5p treatment, hippocampal-dependent spatial learning paradigms, including the standard Morris water maze and a working memory analysis, showed a significant prevention from impairments induced by Abeta deposits in the dorsal hippocampus. Thus, it is possible that a noninvasive treatment such as the one presented here with beta-sheet breaker peptides may be used as a potential therapy for AD patients.
Assuntos
Peptídeos beta-Amiloides/farmacologia , Peptídeos beta-Amiloides/toxicidade , Amiloidose/patologia , Hipocampo/patologia , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/prevenção & controle , Nootrópicos/farmacologia , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/toxicidade , Comportamento Espacial/efeitos dos fármacos , Doença de Alzheimer , Amiloide/análise , Peptídeos beta-Amiloides/administração & dosagem , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/uso terapêutico , Amiloidose/psicologia , Animais , Astrócitos/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Injeções , Injeções Intraperitoneais , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/induzido quimicamente , Nootrópicos/uso terapêutico , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/uso terapêutico , Estrutura Secundária de Proteína/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tempo de Reação , Comportamento Espacial/fisiologia , Técnicas EstereotáxicasRESUMO
Human cellular prion protein (PrP(C)) is involved in several neurodegenerative disorders; however, its normal function is unknown. We report here that a synthetic peptide corresponding to the four-octarepeat sequence of the PrP(C) (PrP(59-91)) protects hippocampal neurons against copper neurotoxic effects in vivo. Using a rat bilateral intrahippocampal injection model, we found that PrP(59-91) protects against copper-induced neurotoxicity, including a recovery in spatial learning performance and a reduced neuronal cell loss and astrogliosis. Previous studies from our laboratory indicated that a tryptophan (Trp) residue plays a key role in the reduction of copper(II) to copper(I); therefore several PrP(59-91) fragments lacking histidine (His) and Trp residues were tested for their capacity to protect from copper toxicity. A PrP(59-91) peptide lacking His residue shows as much neuroprotection as the native peptide; however, PrP(59-91) without Trp residues only partially protected against copper toxicity. The neuroprotective effect not only occurs with PrP(59-91), in fact a full neuroprotection was also observed using just one octamer of the N-terminal region of prion protein. We conclude that the N-terminal tandem octarepeat of the human PrP(C) protects neurons against copper toxicity by a differential contribution of the binding (His) and reducing (Trp) copper activities of PrP(59-91). Our results are consistent with the idea that PrP(C) function is related to copper homeostasis.
Assuntos
Cobre/toxicidade , Memória/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Príons/farmacologia , Percepção Espacial/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiologia , Injeções Intraventriculares , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Dados de Sequência Molecular , Neurotoxinas/farmacologia , Fragmentos de Peptídeos/química , Príons/química , Ratos , Ratos Sprague-DawleyRESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is probably caused by the cytotoxic effect of the amyloid beta-peptide (Abeta). We report here molecular changes induced by Abeta, both in neuronal cells in culture and in rats injected in the dorsal hippocampus with preformed Abeta fibrils, as an in vivo model of the disease. Results indicate that in both systems, Abeta neurotoxicity resulted in the destabilization of endogenous levels of beta-catenin, a key transducer of the Wnt signaling pathway. Lithium chloride, which mimics Wnt signaling by inhibiting glycogen synthase kinase-3beta promoted the survival of post-mitotic neurons against Abeta neurotoxicity and recovered cytosolic beta-catenin to control levels. Moreover, the neurotoxic effect of Abeta fibrils was also modulated with protein kinase C agonists/inhibitors and reversed with conditioned medium containing the Wnt-3a ligand. We also examined the spatial memory performance of rats injected with preformed Abeta fibrils in the Morris water maze paradigm, and found that chronic lithium treatment protected neurodegeneration by rescuing beta-catenin levels and improved the deficit in spatial learning induced by Abeta. Our results are consistent with the idea that Abeta-dependent neurotoxicity induces a loss of function of Wnt signaling components and indicate that lithium or compounds that mimic this signaling cascade may be putative candidates for therapeutic intervention in Alzheimer's patients.
Assuntos
Doença de Alzheimer/metabolismo , Degeneração Neural/metabolismo , Proteínas/metabolismo , Transdução de Sinais/fisiologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Proteínas do Citoesqueleto/metabolismo , Humanos , Isoenzimas/metabolismo , Rim/citologia , Lítio/farmacologia , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Camundongos , Degeneração Neural/tratamento farmacológico , Degeneração Neural/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Proteína Quinase C/metabolismo , Proteínas/genética , Ratos , Ratos Sprague-Dawley , Transativadores/metabolismo , Transfecção , Proteínas Wnt , Proteína Wnt3 , Proteína Wnt3A , beta CateninaRESUMO
Acetylcholinesterase (AChE) has been found to be associated with the core of senile plaques. We have shown that AChE interacts with the amyloid beta-peptide (Abeta) and promotes amyloid fibril formation by a hydrophobic environment close to the peripheral anionic binding site (PAS) of the enzyme. Here we present evidence for the structural motif of AChE involved in this interaction. First, we modeled the docking of Abeta onto the structure of Torpedo californica AChE, and identified four potential sites for AChE-Abeta complex formation. One of these, Site I, spans a major hydrophobic sequence exposed on the surface of AChE, which had been previously shown to interact with liposomes [Shin et al. (1996) Protein Sci. 5, 42-51]. Second, we examined several AChE-derived peptides and found that a synthetic 35-residue peptide corresponding to the above hydrophobic sequence was able to promote amyloid formation. We also studied the ability to promote amyloid formation of two synthetic 24-residue peptides derived from the sequence of a Omega-loop, which has been suggested as an AChE-Abeta interacting motif. Kinetic analyses indicate that only the 35-residue hydrophobic peptide mimics the effect of intact AChE on amyloid formation. Moreover, RP-HPLC analysis revealed that the 35-residue peptide was incorporated into the growing Abeta-fibrils. Finally, fluorescence binding studies showed that this peptide binds Abeta with a K(d) = 184 microM, independent of salt concentration, indicating that the interaction is primarily hydrophobic. Our results indicate that the homologous human AChE motif is capable of accelerating Abeta fibrillogenesis.
Assuntos
Acetilcolinesterase/química , Peptídeos beta-Amiloides/química , Placa Amiloide/química , Acetilcolinesterase/isolamento & purificação , Sequência de Aminoácidos , Animais , Química Encefálica , Bovinos , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Placa Amiloide/ultraestrutura , Conformação Proteica , Solubilidade , TorpedoRESUMO
Extensive neuronal cell loss is observed in Alzheimer's disease. Laminin immunoreactivity colocalizes with senile plaques, the characteristic extracellular histopathological lesions of Alzheimer brain, which consist of the amyloid ß (Aß) peptide polymerized into amyloid fibrils. These lesions have neurotoxic effects and have been proposed to be a main cause of neurodegeneration. In order to understand the pathological significance of the interaction between laminin and amyloid, we investigated the effect of laminin on amyloid structure and toxicity. We found that laminin interacts with the Aß1-40 peptide, blocking fibril formation and even inducing depolymerization of preformed fibrils. Protofilaments known to be intermediate species of Aß fibril formation were also detected as intermediate species of laminin-induced Aß fibril depolymerization. Moreover, laminin-amyloid interactions inhibited the toxic effects on rat primary hippocampal neurons. As a whole, our results indicate a putative anti-amyloidogenic role of laminin which may be of biological and therapeutic interest for controlling amyloidosis, such as those observed in cerebral angiopathy and Alzheimer's disease
Assuntos
Humanos , Animais , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/metabolismo , Matriz Extracelular/metabolismo , Laminina/metabolismo , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/toxicidade , Amiloidose/metabolismo , Laminina/farmacologiaRESUMO
Extensive neuronal cell loss is observed in Alzheimer's disease. Laminin immunoreactivity colocalizes with senile plaques, the characteristic extracellular histopathological lesions of Alzheimer brain, which consist of the amyloid beta (A(beta)) peptide polymerized into amyloid fibrils. These lesions have neurotoxic effects and have been proposed to be a main cause of neurodegeneration. In order to understand the pathological significance of the interaction between laminin and amyloid, we investigated the effect of laminin on amyloid structure and toxicity. We found that laminin interacts with the A(beta)1-40 peptide, blocking fibril formation and even inducing depolymerization of preformed fibrils. Protofilaments known to be intermediate species of A(beta) fibril formation were also detected as intermediate species of laminin-induced A(beta) fibril depolymerization. Moreover, laminin-amyloid interactions inhibited the toxic effects on rat primary hippocampal neurons. As a whole, our results indicate a putative anti-amyloidogenic role of laminin which may be of biological and therapeutic interest for controlling amyloidosis, such as those observed in cerebral angiopathy and Alzheimer's disease.
Assuntos
Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/fisiologia , Matriz Extracelular/fisiologia , Laminina/fisiologia , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Animais , Matriz Extracelular/metabolismo , Humanos , Laminina/farmacologiaRESUMO
Alzheimer's disease (AD) is a neurodegenerative disease with progressive dementia accompanied by three main structural changes in the brain: diffuse loss of neurons; intracellular protein deposits termed neurofibrillary tangles (NFT) and extracellular protein deposits termed amyloid or senile plaques, surrounded by dystrophic neurites. Two major hypotheses have been proposed in order to explain the molecular hallmarks of the disease: The 'amyloid cascade' hypothesis and the 'neuronal cytoskeletal degeneration' hypothesis. While the former is supported by genetic studies of the early-onset familial forms of AD (FAD), the latter revolves around the observation in vivo that cytoskeletal changes - including the abnormal phosphorylation state of the microtubule associated protein tau - may precede the deposition of senile plaques. Recent studies have suggested that the trafficking process of membrane associated proteins is modulated by the FAD-linked presenilin (PS) proteins, and that amyloid beta-peptide deposition may be initiated intracellularly, through the secretory pathway. Current hypotheses concerning presenilin function are based upon its cellular localization and its putative interaction as macromolecular complexes with the cell-adhesion/signaling beta-catenin molecule and the glycogen synthase kinase 3beta (GSK-3beta) enzyme. Developmental studies have shown that PS proteins function as components in the Notch signal transduction cascade and that beta-catenin and GSK-3beta are transducers of the Wnt signaling pathway. Both pathways are thought to have an important role in brain development, and they have been connected through Dishevelled (Dvl) protein, a known transducer of the Wnt pathway. In addition to a review of the current state of research on the subject, we present a cell signaling model in which a sustained loss of function of Wnt signaling components would trigger a series of misrecognition events, determining the onset and development of AD.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais/fisiologia , Proteínas de Peixe-Zebra , Doença de Alzheimer/patologia , Animais , Humanos , Proteínas WntRESUMO
The collagen-like tail of asymmetric acetylcholinesterase (AChE) contains two heparin-binding domains (HBDs) that interact with heparan sulphate proteoglycans, determining the anchoring of the enzyme at the basal lamina and its specific localization at the neuromuscular junction. Both HBDs are characterized by a cluster of basic residues containing a core with the BBXB consensus sequence (where B represents a basic residue and X a non-basic residue). To study the interaction of such HBDs with heparin we have used synthetic peptides to model the N-terminal and C-terminal sites. CD spectroscopy showed that all peptides are triple-helical at low temperatures, and undergo trimer-to-monomer transitions. Displacement assays of asymmetric AChE bound to heparin were performed using the peptides in both monomeric and triple-helical states. In the monomeric conformation, all the peptides were able to displace low levels of AChE depending on the basic charge content. In the triple-helical conformation, peptides containing the consensus sequence showed a large increase in the ability to displace bound AChE. Results suggest that the specific binding of the collagen-like-tail peptides to heparin depends both on the presence of the core sequence and on the triple-helical conformation. Moreover, BBXB-containing peptides that are less stable are more effective in displacing AChE, suggesting that the interaction region needs a significant amount of structural flexibility to better accommodate the ligand.
Assuntos
Acetilcolinesterase/metabolismo , Colágeno/metabolismo , Heparina/metabolismo , Acetilcolinesterase/química , Sequência de Aminoácidos , Dicroísmo Circular , Estabilidade Enzimática , Modelos Químicos , Dados de Sequência Molecular , Ligação Proteica , Conformação Proteica , Homologia de Sequência de AminoácidosRESUMO
One of the theories involved in the etiology of Alzheimer's disease (AD) is the oxidative stress hypothesis. The amyloid beta-peptide (A beta), a hallmark in the pathogenesis of AD and the main component of senile plaques, generates free radicals in a metal-catalyzed reaction inducing neuronal cell death by a reactive oxygen species mediated process which damage neuronal membrane lipids, proteins and nucleic acids. Therefore, the interest in the protective role of different antioxidants in AD such as vitamin E, melatonin and estrogens is growing up. In this review we summarize data that support the involvement of oxidative stress as an active factor in A beta-mediated neuropathology, by triggering or facilitating neurodegeneration, through a wide range of molecular events that disturb neuronal cell homeostasis.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Estresse Oxidativo/fisiologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/toxicidade , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Humanos , Lipídeos de Membrana/metabolismo , Metais/metabolismo , Fármacos Neuroprotetores/farmacologia , Ácidos Nucleicos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Proteínas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Superfície Celular/metabolismoRESUMO
Low density lipoprotein receptor-related protein (LRP) participates in the uptake and degradation of several ligands implicated in neuronal pathophysiology including apolipoprotein E (apoE), activated alpha(2) -macroglobulin (alpha(2)M*) and beta-amyloid precursor protein (APP). The receptor is expressed in a variety of tissues. In the brain LRP is present in pyramidal-type neurons in cortical and hippocampal regions and in astrocytes that are activated as a result of injury or neoplasmic transformation. As LRP is expressed in the monocyte/macrophage cell system, we were interested in examining whether LRP is expressed in microglia. We isolated glial cells from the brain of neonatal rats and LRP was immunodetected both in microglial cells and in astrocytes expressing glial fibrillar acidic protein (GFAP). Microglial cells were able to bind and internalize LRP-specific ligand, alpha(2)M*. The internalization was inhibitable by RAP, with a Kd of 1.7 nM. The expression of LRP was up-regulated by dexamethasone, and down-regulated by lipopolysaccharide (LPS), gamma interferon (IFN-gamma) or a combination of both. LRP was less sensitive to dexamethasone in activated astrocytes than in microglia. We provided the first analysis of LRP expression and regulation in microglia. Our results open the possibility that microglial cells could be related to the participation of LRP and its ligands in different pathophysiological states in brain.
Assuntos
Microglia/metabolismo , Receptores Imunológicos/biossíntese , Receptores de LDL/biossíntese , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Animais Recém-Nascidos , Western Blotting , Células Cultivadas , Dexametasona/farmacologia , Regulação para Baixo/efeitos dos fármacos , Imunofluorescência , Glucocorticoides/farmacologia , Imuno-Histoquímica , Interferon gama/farmacologia , Cinética , Ligantes , Lipopolissacarídeos/farmacologia , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Neuroglia/metabolismo , Testes de Precipitina , Ratos , Regulação para Cima/efeitos dos fármacosRESUMO
Prion protein (PrP) has attracted considerable attention, mainly due to its involvement in transmissible spongiform encephalopathies. Toward its N-terminal region, PrP bears an octapeptide repeat which has been shown to bind copper. We found that a human synthetic peptide (PrP(59-91)), corresponding to the four repeats of Pro-His-Gly-Gly-Gly-Trp-Gly-Gln has the ability to reduce copper. A mutant peptide lacking tryptophan displayed only 24% of the wild-type copper-reducing activity. Experiments performed in a N(2) environment confirmed that O(2) is not involved in the reaction. Our results indicated that cell surface PrP, besides its ability to bind copper, bears the capacity to reduce copper in vitro. The potential physiological role of copper reduction by PrP is discussed.
Assuntos
Cobre/metabolismo , Príons/genética , Sequências de Repetição em Tandem , Triptofano/metabolismo , Humanos , Oxirredução , Oxigênio/metabolismo , Príons/química , Príons/metabolismoRESUMO
The asymmetric form of acetylcholinesterase comprises three catalytic tetramers attached to ColQ, a collagen-like tail responsible for the anchorage of the enzyme to the synaptic basal lamina. ColQ is composed of an N-terminal domain which interacts with the catalytic subunits of the enzyme, a central collagen-like domain and a C-terminal globular domain. In particular, the collagen-like domain of ColQ contains two heparin-binding domains which interact with heparan sulfate proteoglycans in the basal lamina. A three-dimensional model of the collagen-like domain of the tail of asymmetric acetylcholinesterase was constructed. The model presents an undulated shape that results from the presence of a substitution and an insertion in the Gly-X-Y repeating pattern, as well as from low imino-acid regions. Moreover, this model permits the analysis of interactions between the heparin-binding domains of ColQ and heparin, and could also prove useful in the prediction of interaction domains with other putative basal lamina receptors.
Assuntos
Acetilcolinesterase/química , Colágeno/química , Modelos Moleculares , Acetilcolinesterase/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Heparina/metabolismo , Dados de Sequência Molecular , Conformação ProteicaRESUMO
Alzheimer's disease (AD) is characterized by the deposition of amyloid beta-peptide (A beta) and neuronal degeneration in brain regions involved in learning and memory. One of the leading etiologic hypotheses regarding AD is the involvement of free radical-mediated oxidative stress in neuronal degeneration. Recent evidence suggests that metals concentrated in amyloid deposits may contribute to the oxidative insults observed in AD-affected brains. We hypothesized that A beta peptide in the presence of copper enhances its neurotoxicity generating free radicals via copper reduction. In the present study, we have examined the effect of the aggregation state of amyloid-beta-peptide on copper reduction. In independent experiments we measured the copper-reducing ability of soluble and fibrillar A beta(1-40) forms by bathocuproine assays. As it was previously observed for the amyloid precursor protein (APP), the A beta peptide showed copper-reducing ability. The capacity of A beta to reduce copper was independent of the aggregation state. Finally, the A beta peptide derived from the human sequence has a greater effect than the A beta peptide derived from the rat sequence, suggesting that histidine 13 may play a role in copper reduction. In agreement with this possibility, the A beta peptide reduces less copper in the presence of exogenous histidine.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Cobre/metabolismo , Doença de Alzheimer/etiologia , Precursor de Proteína beta-Amiloide/metabolismo , Humanos , Peroxidação de Lipídeos/fisiologia , Oxirredução , Estresse Oxidativo/fisiologiaRESUMO
Alzheimer's disease (AD) is characterized by the deposition of amyloid beta-peptide (A beta) and neuronal degeneration in brain regions involved in learning and memory. One of the leading etiologic hypotheses regarding AD is the involvement of free radical-mediated oxidative stress in neuronal degeneration. Recent evidence suggests that metals concentrated in amyloid deposits may contribute to the oxidative insults observed in AD-affected brains. We hypothesized that A beta peptide in the presence of copper enhances its neurotoxicity generating free radicals via copper reduction. In the present study, we have examined the effect of the aggregation state of amyloid-beta-peptide on copper reduction. In independent experiments we measured the copper-reducing ability of soluble and fibrillar A beta(1-40) forms by bathocuproine assays. As it was previously observed for the amyloid precursor protein (APP), the A beta peptide showed copper-reducing ability. The capacity of A beta to reduce copper was independent of the aggregation state. Finally, the A beta peptide derived from the human sequence has a greater effect than the A beta peptide derived from the rat sequence, suggesting that histidine 13 may play a role in copper reduction. In agreement with this possibility, the A beta peptide reduces less copper in the presence of exogenous histidine.