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1.
Mol Psychiatry ; 22(7): 1002-1008, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28138159

RESUMO

The pathological hallmark of Alzheimer's disease (AD) is accumulation of misfolded amyloid-ß peptides and hyperphosphorylated tau protein in the brain. Increasing evidence suggests that serine-aspartyl proteases-caspases are activated in the AD brain. Previous studies identified a caspase-3 cleavage site within the amyloid-ß precursor protein, and a caspase-3 cleavage of tau as the mechanisms involved in the development of Aß and tau neuropathology, respectively. However, the potential role that caspase-3 could have on tau metabolism remains unknown. In the current studies, we provide experimental evidence that caspase-3 directly and specifically regulates tau phosphorylation, and demonstrate that this effect is mediated by the GSK3ß kinase pathway via a caspase-3-dependent cleavage of the protein kinase B (also known as Akt). In addition, we confirm these results in vivo by using a transgenic mouse model of AD. Collectively, our findings demonstrate a new role for caspase-3 in the neurobiology of tau, and suggest that therapeutic strategies aimed at inhibiting this protease-dependent cleavage of Akt may prove beneficial in preventing tau hyperphosphorylation and subsequent neuropathology in AD and related tauopathies.


Assuntos
Caspase 3/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Neurônios/metabolismo , Proteína Oncogênica v-akt/metabolismo , Fosforilação , Tauopatias/metabolismo , Proteínas tau/metabolismo
2.
Mol Psychiatry ; 22(2): 280-286, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27046648

RESUMO

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder. Although rare genetically linked cases of PD have been reported, most incidences are sporadic in nature. Late-onset, sporadic PD is thought to result from the combined effects of genetic and environmental risk factors exposure. Sleep and circadian rhythm disorders are recurrent among PD patients and appear early in the disease. Although some evidence supports a relationship between circadian disruption (CD) and PD, whether this is secondary to the motor symptoms or, indeed, is a factor that contributes to the pathogenesis of the disease remains to be investigated. In the present paper, we studied the direct consequence of chronic CD on the development of the phenotype in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinen) model of PD. Pre-exposure to CD to mice treated with MPTP resulted in an exacerbation of motor deficit and a significant reduction in the capability of acquiring motor skills. These changes were associated with a greater loss of tyrosine hydroxylase cell content and intense neuroinflammation. Taken together, our findings demonstrate that CD by triggering a robust neuroinflammatory reaction and degeneration of the nigral-dopaminergic neuronal system exacerbates motor deficit. They support the novel hypothesis that circadian rhythm disorder is an environmental risk factor for developing PD.


Assuntos
Transtornos Cronobiológicos/complicações , Ritmo Circadiano/fisiologia , Doença de Parkinson/metabolismo , Animais , Comportamento Animal/fisiologia , Ritmo Circadiano/efeitos dos fármacos , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Degeneração Neural/patologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Fatores de Risco , Tirosina 3-Mono-Oxigenase/metabolismo
3.
Mol Psychiatry ; 21(3): 403-10, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26077691

RESUMO

Dysregulation of stress hormones, such as glucocorticoids, in adult life increases the risk to develop Alzheimer's disease (AD). However, the effect of prenatal glucocorticoids exposure on AD development in the offspring remains unknown. We studied how gestational dexamethasone exposure influences the AD-like phenotype in the offspring of triple transgenic AD mice (3 × Tg). To this end, female mice received dexamethasone or vehicle during the entire pregnancy time in the drinking water. Offspring from vehicle-treated 3 × Tg (controls) were compared with offspring from dexamethasone-treated 3 × Tg later in life for their memory, learning ability and brain pathology. Compared with controls, offspring from dexamethasone-treated mothers displayed improvement in their memory as assessed by fear conditioning test, both in the cue and recall phases. The same animals had a significant reduction in the insoluble fraction of tau, which was associated with an increase in autophagy. In addition, they showed an activation of the transcription factor cellular response element-binding protein and an increase in brain-derived neurotrophic factor and c-FOS protein levels, key regulators of synaptic plasticity and memory. We conclude that dexamethasone exposure during pregnancy provides long-lasting protection against the onset and development of the AD-like phenotype by improving cognition and tau pathology.


Assuntos
Doença de Alzheimer/complicações , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/prevenção & controle , Dexametasona/uso terapêutico , Tauopatias/etiologia , Tauopatias/prevenção & controle , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Exposição Materna , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Gravidez , Presenilina-1/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteínas tau/genética
4.
Transl Psychiatry ; 7(1): e1020, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-28140402

RESUMO

Clinical investigations have highlighted a biological link between reduced brain glucose metabolism and Alzheimer's disease (AD). Previous studies showed that glucose deprivation may influence amyloid beta formation in vivo but no data are available on the effect that this condition might have on tau protein metabolism. In the current paper, we investigated the effect of glucose deficit on tau phosphorylation, memory and learning, and synaptic function in a transgenic mouse model of tauopathy, the h-tau mice. Compared with controls, h-tau mice with brain glucose deficit showed significant memory impairments, reduction of synaptic long-term potentiation, increased tau phosphorylation, which was mediated by the activation of P38 MAPK Kinase pathway. We believe our studies demonstrate for the first time that reduced glucose availability in the central nervous system directly triggers behavioral deficits by promoting the development of tau neuropathology and synaptic dysfunction. Since restoring brain glucose levels and metabolism could afford the opportunity to positively influence the entire AD phenotype, this approach should be considered as a novel and viable therapy for preventing and/or halting the disease progression.


Assuntos
Comportamento Animal , Encéfalo/metabolismo , Glucose/metabolismo , Tauopatias/metabolismo , Doença de Alzheimer , Animais , Encéfalo/fisiopatologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiopatologia , Desoxiglucose , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Aprendizagem/fisiologia , Potenciação de Longa Duração/fisiologia , Masculino , Memória/fisiologia , Camundongos , Camundongos Transgênicos , Neurônios , Fosforilação , Distribuição Aleatória , Sinapses/metabolismo , Sinapses/fisiologia , Tauopatias/genética , Tauopatias/fisiopatologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas tau/genética
5.
Transl Psychiatry ; 6: e733, 2016 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-26859816

RESUMO

Environmental stressor exposure is associated with a variety of age-related diseases including neurodegeneration. Although the initial events of sporadic Parkinson's disease (PD) are not known, consistent evidence supports the hypothesis that the disease results from the combined effect of genetic and environmental risk factors. Among them, behavioral stress has been shown to cause damage and neuronal loss in different areas of the brain, however, its effect on the dopaminergic system and PD pathogenesis remains to be characterized. The C57BL/6 mice underwent chronic restraint/isolation (RI) stress and were then treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), whereas the control mice were treated only with MPTP and the effect on the PD-like phenotype was evaluated. The mice that underwent RI before the administration of MPTP manifested an exaggerated motor deficit and impairment in the acquisition of motor skills, which were associated with a greater loss of neuronal tyrosine hydroxylase and astrocytes activation. By showing that RI influences the onset and progression of the PD-like phenotype, our study underlines the novel pathogenetic role that chronic behavioral stressor has in the disease process by triggering neuroinflammation and degeneration of the nigral dopaminergic system.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Encéfalo/fisiopatologia , Inflamação/fisiopatologia , Transtornos Motores/fisiopatologia , Doença de Parkinson/fisiopatologia , Estresse Psicológico/fisiopatologia , Animais , Comportamento Animal/fisiologia , Doença Crônica , Modelos Animais de Doenças , Feminino , Inflamação/complicações , Inflamação/psicologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transtornos Motores/complicações , Transtornos Motores/psicologia , Doença de Parkinson/complicações , Doença de Parkinson/psicologia , Estresse Psicológico/complicações , Estresse Psicológico/psicologia
6.
Transl Psychiatry ; 3: e333, 2013 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-24301651

RESUMO

FLAP (5-lipoxygenase-activating protein) is a protein widely distributed within the central nervous system whose function is to regulate the activation of the 5-Lipoxygenase enzyme. Although previous works show that pharmacological blockade of FLAP improve the amyloidotic phenotype of the Tg2576, its contribution to tau pathology remains to be investigated. In the present paper, we studied the effect of FLAP pharmacological inhibition on the metabolism of endogenous tau in these mice. Total tau levels in the brains of mice receiving MK-591, a selective and specific FLAP inhibitor, were not changed when compared with controls. By contrast, treated animals had a significant reduction of tau phosphorylation at specific sites: Ser396; Ser396/Ser404; and Thr 231/Ser 235. This reduction was associated with a significant decrease in the activity of glycogen synthase kinase-3 beta, but not other kinases. In addition, MK-591-treated mice had a significant increase in the post-synaptic density protein-95 and the dendritic protein microtubule-associated protein 2. These data establish a novel functional role for FLAP in the metabolism of tau, and together with its known Aß modulatory effect they suggest that its pharmacological inhibition could represent a novel therapeutic opportunity for Alzheimer's disease.


Assuntos
Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacologia , Proteínas Ativadoras de 5-Lipoxigenase/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Encéfalo/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/efeitos dos fármacos , Indóis/farmacologia , Quinolinas/farmacologia , Proteínas tau/efeitos dos fármacos , Proteínas Ativadoras de 5-Lipoxigenase/metabolismo , Doença de Alzheimer/enzimologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Proteína 4 Homóloga a Disks-Large , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Guanilato Quinases/efeitos dos fármacos , Guanilato Quinases/metabolismo , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas tau/metabolismo
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