Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nat Med ; 22(11): 1268-1276, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27723722

RESUMO

In Alzheimer's disease (AD) and other tauopathies, the tau protein forms fibrils, which are believed to be neurotoxic. However, fibrillar tau has been dissociated from neuron death and network dysfunction, suggesting the involvement of nonfibrillar species. Here we describe a novel pathological process in which caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, Δtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with AD. The expression of tau mutants that resisted caspase-2 cleavage prevented tau from infiltrating spines, dislocating glutamate receptors and impairing synaptic function in cultured neurons, and it prevented memory deficits and neurodegeneration in mice. Decreasing the levels of caspase-2 restored long-term memory in mice that had existing deficits. Our results suggest an overall treatment strategy for re-establishing synaptic function and restoring memory in patients with AD by preventing tau from accumulating in dendritic spines.


Assuntos
Doença de Alzheimer/metabolismo , Caspase 2/metabolismo , Espinhas Dendríticas/metabolismo , Hipocampo/metabolismo , Transtornos da Memória/metabolismo , Memória , Neurônios/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Animais , Western Blotting , Caspases/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores , Hipocampo/citologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Transtornos da Memória/genética , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Transgênicos , Morfolinos , Neurônios/citologia , Tamanho do Órgão , Receptores de Glutamato/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sinapses , Proteínas tau/genética
2.
J Vis Exp ; (100): e52706, 2015 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-26132096

RESUMO

The Morris water maze (MWM) is a commonly used task to assess hippocampal-dependent spatial learning and memory in transgenic mouse models of disease, including neurocognitive disorders such as Alzheimer's disease. However, the background strain of the mouse model used can have a substantial effect on the observed behavioral phenotype, with some strains exhibiting superior learning ability relative to others. To ensure differences between transgene negative and transgene positive mice can be detected, identification of a training procedure sensitive to the background strain is essential. Failure to tailor the MWM protocol to the background strain of the mouse model may lead to under- or over- training, thereby masking group differences in probe trials. Here, a MWM protocol tailored for use with the F1 FVB/N x 129S6 background is described. This is a frequently used background strain to study the age-dependent effects of mutant P301L tau (rTg(TauP301L)4510 mice) on the memory deficits associated with Alzheimer's disease. Also described is a strategy to re-optimize, as dictated by the particular testing environment utilized.


Assuntos
Doença de Alzheimer/fisiopatologia , Modelos Animais de Doenças , Aprendizagem em Labirinto , Animais , Feminino , Masculino , Camundongos , Camundongos Transgênicos
3.
Cell Rep ; 11(11): 1760-71, 2015 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-26051935

RESUMO

The accumulation of amyloid-ß (Aß) as amyloid fibrils and toxic oligomers is an important step in the development of Alzheimer's disease (AD). However, there are numerous potentially toxic oligomers and little is known about their neurological effects when generated in the living brain. Here we show that Aß oligomers can be assigned to one of at least two classes (type 1 and type 2) based on their temporal, spatial, and structural relationships to amyloid fibrils. The type 2 oligomers are related to amyloid fibrils and represent the majority of oligomers generated in vivo, but they remain confined to the vicinity of amyloid plaques and do not impair cognition at levels relevant to AD. Type 1 oligomers are unrelated to amyloid fibrils and may have greater potential to cause global neural dysfunction in AD because they are dispersed. These results refine our understanding of the pathogenicity of Aß oligomers in vivo.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide/metabolismo , Agregação Patológica de Proteínas/metabolismo , Estrutura Quaternária de Proteína , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/classificação , Animais , Humanos , Camundongos , Placa Amiloide/química
4.
Neuron ; 68(6): 1067-81, 2010 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-21172610

RESUMO

The microtubule-associated protein tau accumulates in Alzheimer's and other fatal dementias, which manifest when forebrain neurons die. Recent advances in understanding these disorders indicate that brain dysfunction precedes neurodegeneration, but the role of tau is unclear. Here, we show that early tau-related deficits develop not from the loss of synapses or neurons, but rather as a result of synaptic abnormalities caused by the accumulation of hyperphosphorylated tau within intact dendritic spines, where it disrupts synaptic function by impairing glutamate receptor trafficking or synaptic anchoring. Mutagenesis of 14 disease-associated serine and threonine amino acid residues to create pseudohyperphosphorylated tau caused tau mislocalization while creation of phosphorylation-deficient tau blocked the mistargeting of tau to dendritic spines. Thus, tau phosphorylation plays a critical role in mediating tau mislocalization and subsequent synaptic impairment. These data establish that the locus of early synaptic malfunction caused by tau resides in dendritic spines.


Assuntos
Espinhas Dendríticas/metabolismo , Degeneração Neural/metabolismo , Sinapses/metabolismo , Proteínas tau/metabolismo , Animais , Células Cultivadas , Espinhas Dendríticas/química , Espinhas Dendríticas/fisiologia , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Transgênicos , Degeneração Neural/fisiopatologia , Fosforilação/fisiologia , Ratos , Sinapses/química , Sinapses/fisiologia , Proteínas tau/fisiologia
5.
Behav Brain Res ; 212(1): 115-20, 2010 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-20381538

RESUMO

The most widely used mouse model of Alzheimer's disease is the Tg2576 (APP(SWE)) model. While general agreement about their neuropathology prevails, disparate results concerning cognitive changes have been reported. To resolve this controversy, we combined Morris water maze data collected over >10 years to determine the extent of memory impairment. APP(SWE) mice exhibited an age-dependent decline in memory, but the effect size was small when compared to non-transgenic littermates. Larger effect sizes were achieved when comparing APP(SWE) and Tg5469 (APP(WT)) mice.


Assuntos
Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/etiologia , Fatores Etários , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Análise de Variância , Animais , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/genética , Humanos , Masculino , Transtornos da Memória/genética , Camundongos , Camundongos Transgênicos , Mutação/genética , Fatores Sexuais
6.
Brain ; 131(Pt 3): 651-64, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18292081

RESUMO

Non-steroidal anti-inflammatory agents (NSAIDs) are associated with a marked reduction in the risk of developing Alzheimer's disease, a form of dementia characterized by the accumulation of amyloid plaques containing the amyloid-beta protein (Abeta). Studies of the effects of NSAIDs upon the inflammatory response surrounding amyloid plaques and upon the generation of Abeta from the amyloid precursor protein (APP) have led to two proposed mechanisms by which NSAIDs may protect against Alzheimer's disease: one, the selective lowering of Abeta42 by a subset of NSAIDs; and two, the reduction of inflammation. Although Alzheimer's disease is a disorder of brain and synaptic function, the effects of NSAIDs on Abeta-mediated suppression of synaptic plasticity and memory function have never been reported. We therefore investigated how three different NSAIDs, chosen for their distinct effects on Abeta42 production and the inhibition of the cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, affect memory function and synaptic plasticity. By focusing upon brain and synapse function, we made novel observations about the effects of NSAIDs on Abeta-mediated neural processes. Here we report that the selective inhibition of COX-2, but not COX-1, acutely prevented the suppression of hippocampal long-term plasticity (LTP) by Abeta. The non-selective NSAIDs, ibuprofen and naproxen, and a selective COX-2 inhibitor, MF-tricyclic, each restored memory function in Tg2576 mice over-expressing APP, and also blocked Abeta-mediated inhibition of LTP. There was no advantage of ibuprofen, a selective Abeta42-lowering agent (SALA), over the non-SALAs, naproxen and MF-tricyclic. The beneficial effects on memory did not depend upon lowered levels of Abeta42 or the inflammatory cytokines, tumour necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). Intriguingly, improved memory function was inversely related to prostaglandin E2 (PGE2) levels. Conversely, exogenous PGE2 prevented the restorative effects of COX-2 inhibitors on LTP. The data indicate that the inhibition of COX-2 blocks Abeta-mediated suppression of LTP and memory function, and that this block occurs independently of reductions in Abeta42 or decreases in inflammation. The results lead us to propose a third possible mechanism by which NSAIDs may protect against Alzheimer's disease, involving the blockade of a COX-2-mediated PGE2 response at synapses.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Inibidores de Ciclo-Oxigenase 2/farmacologia , Memória/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Peptídeos beta-Amiloides/farmacologia , Animais , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Ciclo-Oxigenase/uso terapêutico , Dinoprostona/fisiologia , Furanos/farmacologia , Furanos/uso terapêutico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ibuprofeno/farmacologia , Ibuprofeno/uso terapêutico , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Transtornos da Memória/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Naproxeno/farmacologia , Naproxeno/uso terapêutico , Fragmentos de Peptídeos/farmacologia , Ratos , Sinapses/fisiologia , Fator de Necrose Tumoral alfa/metabolismo
7.
J Neurosci ; 22(15): 6331-5, 2002 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-12151510

RESUMO

Alzheimer's disease (AD) is a neurodegenerative condition, believed to be irreversible, characterized by inexorable deterioration of memory and intellect, with neuronal loss accompanying amyloid plaques and neurofibrillary tangles. In an amyloid precursor protein transgenic mouse model, Tg2576, little or no neuronal loss accompanies age-related memory impairment or the accumulation of Abeta, a 40-42 aa polypeptide found in plaques. Recently, we have shown inverse correlations between brain Abeta and memory in Tg2576 mice stratified by age (Westerman et al., 2002). Broadening the age range examined obscured this relationship, leading us to propose that small, soluble assemblies of Abeta disrupt cognitive function in these mice. Here we show that memory loss can be fully reversed in Tg2576 mice using intraperitoneally administered BAM-10, a monoclonal antibody recognizing the N terminus of Abeta. The beneficial effect of BAM-10 was not associated with a significant Abeta reduction, but instead eliminated the inverse relationship between brain Abeta and memory. We postulate that BAM-10 acts by neutralizing Abeta assemblies in the brain that impair cognitive function. Our results indicate that a substantial portion of memory loss in Tg2576 mice is not permanent. If these Abeta assemblies contribute significantly to memory loss in AD, then successfully targeting them might improve memory in some AD patients.


Assuntos
Doença de Alzheimer/fisiopatologia , Transtornos da Memória/fisiopatologia , Envelhecimento/metabolismo , Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/análise , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Anticorpos Monoclonais/farmacologia , Comportamento Animal/efeitos dos fármacos , Química Encefálica , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Imunização Passiva/métodos , Injeções Intraperitoneais , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória/complicações , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Indução de Remissão/métodos , Comportamento Espacial/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...