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1.
Br J Pharmacol ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034757

RESUMO

BACKGROUND AND PURPOSE: Immunotherapeutic intervention is one of the most promising strategies for the prevention and treatment of Alzheimer's disease (AD). Although they showed great success in AD mouse models, the clinical trials of many immune approaches failed due to low efficacy and safety. Thus, an animal model which can show the potential side effects of vaccines or antibodies is urgently needed. In this study, we generated EAE/AD mice by crossing APP/PS1 mice with experimental autoimmune encephalomyelitis (EAE) mice. We then investigated the efficacy and safety of two vaccines: the immunogens of which were Aß1-42 aggregates (Aß42 vaccine) and an oligomer-specific conformational epitope (AOE1 vaccine), respectively. EXPERIMENTAL APPROACH: EAE/AD mice were immunized with the Aß42 vaccine or AOE1 vaccine five times at biweekly intervals. After the final immunization, cognitive function was evaluated by the Morris water maze, Y maze, and object recognition tests. Neuropathological changes in the mouse brains were analysed by immunohistochemistry and ELISA. KEY RESULTS: In contrast to previous findings in conventional AD animal models, Aß42 immunization promoted neuroinflammation, enhanced Aß levels and plaque burden, and failed to restore cognitive deficits in EAE/AD mice. By contrast, AOE1 immunization dramatically attenuated neuroinflammation, reduced Aß levels, and improved cognitive performance in EAE/AD mice. CONCLUSION AND IMPLICATIONS: These results suggest that the EAE/AD mouse model can exhibit the potential side effects of AD immune approaches that conventional AD animal models fail to display. Furthermore, strategies specifically targeting Aß oligomers may be safe and show clinical benefit for AD treatment.

2.
Sci Rep ; 6: 36631, 2016 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-27824125

RESUMO

Overproduction or poor clearance of amyloids lead to amyloid aggregation and even amyloidosis development. Different amyloids may interact synergistically to promote their aggregation and accelerate pathology in amyloidoses. Amyloid oligomers assembled from different amyloids share common structures and epitopes, and are considered the most toxic species in the pathologic processes of amyloidoses, which suggests that an agent targeting the common epitope of toxic oligomers could provide benefit to several amyloidoses. In this study, we firstly showed that an oligomer-specific single-chain variable fragment antibody, W20 simultaneously improved motor and cognitive function in Parkinson's disease and Huntington's disease mouse models, and attenuated a number of neuropathological features by reducing α-synuclein and mutant huntingtin protein aggregate load and preventing synaptic degeneration. Neuroinflammation and oxidative stress in vivo were also markedly inhibited. The proposed strategy targeting the common epitopes of amyloid oligomers presents promising potential for treating Parkinson's disease, Huntington's disease, Alzheimer's disease, and other amyloidoses.


Assuntos
Amiloide/imunologia , Amiloidose/tratamento farmacológico , Cognição/efeitos dos fármacos , Epitopos/imunologia , Atividade Motora/efeitos dos fármacos , Anticorpos de Cadeia Única/farmacologia , Amiloidose/imunologia , Amiloidose/patologia , Amiloidose/fisiopatologia , Animais , Doença de Huntington/tratamento farmacológico , Doença de Huntington/imunologia , Doença de Huntington/fisiopatologia , Masculino , Camundongos , Camundongos Mutantes , Atividade Motora/imunologia , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson Secundária/imunologia , Doença de Parkinson Secundária/fisiopatologia , Anticorpos de Cadeia Única/imunologia
3.
Behav Brain Res ; 296: 109-117, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26358659

RESUMO

The pathologies of Alzheimer's disease (AD) is associated with soluble beta-amyloid (Aß) oligomers, neuroinflammation and oxidative stress. Decreasing the levels of Aß oligomer, glial activation and oxidative stress are potential therapeutic approaches for AD treatment. We previously found alpha-tocopherol quinine (α-TQ) inhibited Aß aggregation and cytotoxicity, decreased the release of inflammatory cytokines and reactive oxygen species (ROS) in vitro. However, whether α-TQ ameliorates memory deficits and other neuropathologies in mice or patients with AD remains unknown. In this study, we reported that orally administered α-TQ ameliorated memory impairment in APPswe/PS1dE9 transgenic mice, decreased oxidative stress and the levels of Aß oligomer in the brains of mice, prevented the production of inducible nitric oxide synthase and inflammatory mediators, such as interleukin-6 and interleukin-1ß, and inhibited microglial activation by inhibiting NF-κB signaling pathway. These findings suggest that α-TQ has potential therapeutic value for AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , NF-kappa B/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Vitamina E/análogos & derivados , Peptídeos beta-Amiloides , Animais , Antioxidantes/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Interleucinas/metabolismo , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Vitamina E/administração & dosagem , Vitamina E/farmacologia
4.
Food Funct ; 6(10): 3296-306, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26242245

RESUMO

Recent evidence showed that amylin deposition is not only found in the pancreas in type 2 diabetes mellitus (T2DM) patients, but also in other peripheral organs, such as kidneys, heart and brain. Circulating amylin oligomers that cross the blood-brain barrier and accumulate in the brain may be an important contributor to diabetic cerebral injury and neurodegeneration. Moreover, increasing epidemiological studies indicate that there is a significant association between T2DM and Alzheimer's disease (AD). Amylin and ß-amyloid (Aß) may share common pathophysiology and show strikingly similar neurotoxicity profiles in the brain. To explore the potential effects of rutin on AD, we here investigated the effect of rutin on amylin aggregation by thioflavin T dyeing, evaluated the effect of rutin on amylin-induced neurocytotoxicity by the MTT assay, and assessed oxidative stress, as well as the generation of nitric oxide (NO) and pro-inflammatory cytokines in neuronal cells. Our results showed that the flavonoid antioxidant rutin inhibited amylin-induced neurocytotoxicity, decreased the production of reactive oxygen species (ROS), NO, glutathione disulfide (GSSG), malondialdehyde (MDA) and pro-inflammatory cytokines TNF-α and IL-1ß, attenuated mitochondrial damage and increased the GSH/GSSG ratio. These protective effects of rutin may have resulted from its ability to inhibit amylin aggregation, enhance the antioxidant enzyme activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) and reduce inducible nitric oxide synthase (iNOS) activity. These in vitro results indicate that rutin is a promising natural product for protecting neuronal cells from amylin-induced neurotoxicity and oxidative stress, and rutin administration could be a feasible therapeutic strategy for preventing AD development and protecting the aging brain or slowing neurodegenerative processes.


Assuntos
Polipeptídeo Amiloide das Ilhotas Pancreáticas/toxicidade , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Rutina/farmacologia , Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Barreira Hematoencefálica , Catalase/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dissulfeto de Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Interleucina-1beta/metabolismo , Malondialdeído/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
Free Radic Biol Med ; 74: 50-63, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24960578

RESUMO

Alzheimer disease (AD) is characterized by extracellular senile plaques, intracellular neurofibrillary tangles, and memory loss. Aggregated amyloid-ß (Aß), oxidative stress, and inflammation have pivotal roles in the pathogenesis of AD. Therefore, the inhibition of Aß-induced neurotoxicity, oxidative stress, and inflammation is a potential therapeutic strategy for the treatment of AD. In this study, a heptapeptide, isolated from a Ph.D.-C7C library by phage display, attenuated Aß42-induced cytotoxicity in SH-SY5Y neuroblastoma cells and reduced Aß42-induced oxidative stress by decreasing the production of reactive oxygen species and glutathione disulfide. As a result, glutathione level increased and superoxide dismutase and glutathione peroxidase activities were enhanced in vitro and in vivo. This peptide also suppressed the inflammatory response by decreasing the release of proinflammatory cytokines, such as tumor necrosis factor α and interleukin 1ß, in microglia and by reducing microgliosis and astrogliosis in AD transgenic mice. This peptide was intracerebroventricularly administered to APPswe/PS1dE9 transgenic mice. We found that this peptide significantly improved spatial memory and reduced the amyloid plaque burden and soluble and insoluble Aß levels. Our findings suggest that this multifunctional peptide has therapeutic potential for an Aß-targeted treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Transtornos da Memória/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/antagonistas & inibidores , Doença de Alzheimer/psicologia , Sequência de Aminoácidos , Peptídeos beta-Amiloides/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Dissulfeto de Glutationa/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/patologia , Dados de Sequência Molecular , Oligopeptídeos/química , Fragmentos de Peptídeos/metabolismo , Biblioteca de Peptídeos , Espécies Reativas de Oxigênio/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
6.
PLoS One ; 9(4): e94197, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24718459

RESUMO

Beta-amyloid (Aß) aggregates have a pivotal role in pathological processing of Alzheimer's disease (AD). The clearance of Aß monomer or aggregates is a causal strategy for AD treatment. Microglia and astrocytes are the main macrophages that exert critical neuroprotective roles in the brain. They may effectively clear the toxic accumulation of Aß at the initial stage of AD, however, their functions are attenuated because of glial overactivation. In this study, we first showed that heptapeptide XD4 activates the class A scavenger receptor (SR-A) on the glia by increasing the binding of Aß to SR-A, thereby promoting glial phagocytosis of Aß oligomer in microglia and astrocytes and triggering intracellular mitogen-activated protein kinase (MAPK) signaling cascades. Moreover, XD4 enhances the internalization of Aß monomers to microglia and astrocytes through macropinocytosis or SR-A-mediated phagocytosis. Furthermore, XD4 significantly inhibits Aß oligomer-induced cytotoxicity to glial cells and decreases the production of proinflammatory cytokines, such as TNF-α and IL-1ß, in vitro and in vivo. Our findings may provide a novel strategy for AD treatment by activating SR-A.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Astrócitos/metabolismo , Microglia/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptídeos/farmacologia , Receptores Depuradores/fisiologia , Receptores Depuradores Classe A/fisiologia , Animais , Astrócitos/efeitos dos fármacos , Astrocitoma/patologia , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , Córtex Cerebral/citologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Interleucina-1beta/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Ratos , Fator de Necrose Tumoral alfa/metabolismo
7.
Behav Brain Res ; 264: 173-80, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24512768

RESUMO

Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by extracellular ß-amyloid (Aß) plaques and intracellular neurofibrillary tangles in the brain. Aß aggregation is closely associated with neurotoxicity, oxidative stress, and neuronal inflammation. The soluble Aß oligomers are believed to be the most neurotoxic form among all forms of Aß aggregates. We have previously reported a polyphenol compound rutin that could inhibit Aß aggregation and cytotoxicity, attenuate oxidative stress, and decrease the production of nitric oxide and proinflammatory cytokines in vitro. In the current study, we investigated the effect of rutin on APPswe/PS1dE9 transgenic mice. Results demonstrated that orally administered rutin significantly attenuated memory deficits in AD transgenic mice, decreased oligomeric Aß level, increased super oxide dismutase (SOD) activity and glutathione (GSH)/glutathione disulfide (GSSG) ratio, reduced GSSG and malondialdehyde (MDA) levels, downregulated microgliosis and astrocytosis, and decreased interleukin (IL)-1ß and IL-6 levels in the brain. These results indicated that rutin is a promising agent for AD treatment because of its antioxidant, anti-inflammatory, and reducing Aß oligomer activities.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Citocinas/metabolismo , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Estresse Oxidativo/efeitos dos fármacos , Rutina/uso terapêutico , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Humanos , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Presenilina-1/genética , Tempo de Reação , Rutina/farmacologia , Fatores de Tempo
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