RESUMO
No treatment options are currently available to counteract cognitive deficits and/or delay progression towards dementia in older people with mild cognitive impairment (MCI). The 'Train the Brain' programme is a combined motor and cognitive intervention previously shown to markedly improve cognitive functions in MCI individuals compared to non-trained MCI controls, as assessed at the end of the 7-month intervention. Here, we extended the previous analyses to include the long-term effects of the intervention and performed a data disaggregation by gender, education and age of the enrolled participants. We report that the beneficial impact on cognitive functions was preserved at the 14-month follow-up, with greater effects in low-educated compared to high-educated individuals, and in women than in men.
Assuntos
Disfunção Cognitiva , Demência , Masculino , Feminino , Humanos , Idoso , Demência/psicologia , Seguimentos , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/terapia , Disfunção Cognitiva/psicologia , Encéfalo , CogniçãoRESUMO
A decrease in brain-derived neurotrophic factor (BDNF), a neurotrophin essential for synaptic function, plasticity and neuronal survival, is evident early in the progression of Alzheimer's disease (AD), being apparent in subjects with mild cognitive impairment or mild AD, and both proBDNF and mature BDNF levels are positively correlated with cognitive measures. BDNF delivery is, therefore, considered of great interest as a potentially useful therapeutic strategy to contrast AD. Invasive BDNF administration has indeed been recently used in animal models of AD with promising results in rescuing memory deficits, synaptic density and cell loss. Here, we tested whether non-invasive intranasal administration of different BDNF concentrations after the onset of cognitive and anatomical deficits (6 months of age) could rescue neuropathological and memory deficits in AD11 mice, a model of NGF deprivation-induced neurodegeneration. In addition to AD hallmarks, we investigated BDNF effects on microglia presence in the brain of AD11 mice, since alterations in microglia activation have been associated with ageing-related cognitive decline and with the progression of neurodegenerative diseases, including AD. We found that intranasal delivery of 42 pmol BDNF (1 µM), but not PBS, was sufficient to completely rescue performance of AD11 mice both in the object recognition test and in the object context test. No further improvement was obtained with 420 pmol (10 µM) BDNF dose. The strong improvement in memory performance in BDNF-treated mice was not accompanied by an amelioration of AD-like pathology, Aß burden, tau hyperphosphorylation and cholinergic deficit, but there was a dramatic decrease of CD11b immunoreactive brain microglia. These results reinforce the potential therapeutic uses of BDNF in AD and the non-invasive intranasal route as an effective delivery strategy of BDNF to the brain. They also strengthen the connection between neuroinflammation and neurodegenerative dementia and suggest microglia as a possible mediator of BDNF therapeutic actions in the brain.
Assuntos
Doença de Alzheimer , Fator Neurotrófico Derivado do Encéfalo , Administração Intranasal , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/uso terapêutico , Modelos Animais de Doenças , Transtornos da Memória/tratamento farmacológico , CamundongosRESUMO
Environmental enrichment (EE) is known to enhance learning and memory. Declarative memories are thought to undergo a first rapid and local consolidation process, followed by a prolonged process of system consolidation, which consist in a time-dependent gradual reorganization of brain regions supporting remote memory storage and crucial for the formation of enduring memories. At present, it is not known whether EE can affect the process of declarative memory system consolidation. We characterized the time course of hippocampal and cortical activation following recall of progressively more remote spatial memories. Wild-type mice either exposed to EE for 40 days or left in standard environment were subjected to spatial learning in the Morris water maze and to the probe test 1, 10, 20, 30, and 50 days after learning. Following the probe test, regional expression of the inducible immediate early gene c-Fos was mapped by immunohistochemistry, as an indicator of neuronal activity. We found that activation of the medial prefrontal cortex (mPFC), suggested to have a privileged role in processing remote spatial memories, was evident at shorter time intervals after learning in EE mice; in addition, EE induced the progressive activation of a distributed cortical network not activated in non-EE mice. This suggests that EE not only accelerates the process of mPFC recruitment but also recruits additional cortical areas into the network supporting remote spatial memories.
Assuntos
Córtex Cerebral/fisiologia , Hipocampo/fisiologia , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Percepção Espacial/fisiologia , Animais , Meio Ambiente , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
One major goal in Neuroscience is the development of strategies promoting neural plasticity in the adult central nervous system, when functional recovery from brain disease and injury is limited. New evidence has underscored a pivotal role for cortical inhibitory circuitries in regulating plasticity both during development and in adulthood. This paper summarizes recent findings showing that the inhibition-excitation balance controls adult brain plasticity and is at the core of the pathogenesis of neurodevelopmental disorders like autism, Down syndrome, and Rett syndrome.
Assuntos
Encéfalo/fisiologia , Inibição Neural/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Ácido gama-Aminobutírico/fisiologia , Transtorno Autístico/fisiopatologia , Síndrome de Down/fisiopatologia , Humanos , Síndrome de Rett/fisiopatologiaRESUMO
Rho family GTPases have been implicated as important regulators of neuronal development. Rac3 is a member of this family specifically expressed in vertebrate developing neurons, where it is coexpressed with the ubiquitous Rac1 GTPase. We have previously shown that Rac3 knockout mice are viable and fertile. The Rac3 protein shows highest expression around postnatal day 7 in brain regions relevant for cognitive behaviors. In this study we find that Rac3 knockout mice do not show defects in spatial reference memory assessed with water maze task, but they show a reduced behavioral flexibility to novel situations. Analysis of explorative behavior revealed hyperactive behavior and hyperreactivity to the presentation of new stimuli, as assessed by dark/light box, emergence and novel object tests. These defects were not due to reduced visual abilities, since visual acuity and contrast sensitivity were comparable in Rac3 knockout and wildtype littermates. Our data reinforce the notion that Rho family GTPases are important for normal cognitive development, and highlight specific functions of Rac3 that cannot be compensated by the coexpressed homologous Rac1.
Assuntos
Comportamento Animal/fisiologia , Comportamento Exploratório/fisiologia , Hipercinese/genética , Hipercinese/fisiopatologia , Proteínas rac de Ligação ao GTP/deficiência , Análise de Variância , Animais , Animais Recém-Nascidos , Anticorpos/farmacologia , Sensibilidades de Contraste/genética , Regulação da Expressão Gênica no Desenvolvimento , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Knockout , Estimulação Luminosa/métodos , Fatores de Tempo , Gravação em Vídeo/métodos , Acuidade Visual/genética , Proteínas rac de Ligação ao GTP/imunologiaRESUMO
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive memory deficits and cognitive decline. We explored the possibility that Environmental Enrichment (EE) may reduce the disease progression in a comprehensive mouse model for AD like neurodegeneration, the AD11 mice. AD11 mice, which express anti nerve growth factor (NGF) antibodies, develop an age dependent neurodegeneration which encompasses all hallmarks of human AD. We have tested the efficacy of EE starting from 2 months of age, that is before the onset of behavioural deficits in AD11 mice. At 7 months of age, visual recognition memory was tested with the Object Recognition Test (ORT), spatial memory with the Morris Water Maze (MWM) and the presence of AD pathological hallmarks (Abeta clusters, presence of hyperphosphorylated tau and cholinergic deficit) was assessed immunohistochemically. We found that in AD11 mice exposed to EE from 2 to 7 months of age performance in both memory tests was significantly better than in non EE AD11 mice and indistinguishable from that in wild-type mice of the same age. Exposure to EE from 2 to 7 months significantly reduce the appearance of AD neuropathological hallmarks. A group of AD11 mice was tested also at 12 months of age: we found that 12 months old AD11 mice exposed to EE from 2 to 7 months of age performed significantly better than non EE AD11 mice of the same age and did not differ from 12 months old wt mice. Thus, EE is able to prevent the onset of memory deficits up to at least 12 months of age and to restrain the progression of neurodegeneration in a mouse model of AD.
Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/prevenção & controle , Meio Ambiente , Transtornos da Memória/prevenção & controle , Degeneração Neural/patologia , Degeneração Neural/prevenção & controle , Estimulação Física , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Anticorpos Monoclonais/metabolismo , Fibras Colinérgicas/metabolismo , Fibras Colinérgicas/patologia , Aprendizagem por Discriminação , Aprendizagem em Labirinto , Camundongos , Degeneração Neural/metabolismo , Reconhecimento Psicológico , Percepção Visual/fisiologiaRESUMO
Down syndrome (DS) is the most common genetic disorder associated with mental retardation. It has been repeatedly shown that Ts65Dn mice, the prime animal model for DS, have severe cognitive and neural plasticity defects due to excessive inhibition. We report that increasing sensory-motor stimulation in adulthood through environmental enrichment (EE) reduces brain inhibition levels and promotes recovery of spatial memory abilities, hippocampal synaptic plasticity, and visual functions in adult Ts65Dn mice.
RESUMO
Neurogenesis continues to occur in the adult mammalian hippocampus and is regulated by both genetic and environmental factors. It is known that exposure to an enriched environment enhances the number of newly generated neurons in the dentate gyrus. However, the mechanisms by which enriched housing produces these effects are poorly understood. To test a role for neurotrophins, we used heterozygous knockout mice for brain-derived neurotrophic factor (BDNF+/-) and mice lacking neurotrophin-4 (NT-4-/-) together with their wild-type littermates. Mice were either reared in standard laboratory conditions or placed in an enriched environment for 8 weeks. Animals received injections of the mitotic marker bromodeoxyuridine (BrdU) to label newborn cells. Enriched wild-type and enriched NT-4-/- mice showed a two-fold increase in hippocampal neurogenesis as assessed by stereological counting of BrdU-positive cells in the dentate gyrus and double labelling for BrdU and the neuronal marker NeuN. Remarkably, this enhancement of hippocampal neurogenesis was not seen in enriched BDNF+/- mice. Failure to up-regulate BDNF accompanied the lack of a neurogenic response in enriched BDNF heterozygous mice. We conclude that BDNF but not NT-4 is required for the environmental induction of neurogenesis.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/fisiologia , Meio Ambiente , Hipocampo/citologia , Neurônios/fisiologia , Organogênese/fisiologia , Animais , Western Blotting/métodos , Fator Neurotrófico Derivado do Encéfalo/deficiência , Bromodesoxiuridina/metabolismo , Contagem de Células/métodos , Expressão Gênica/fisiologia , Imuno-Histoquímica/métodos , Camundongos , Camundongos Knockout , Fatores de Crescimento Neural/deficiência , Fosfopiruvato Hidratase/metabolismoRESUMO
Nerve growth factor (NGF) delivery to the brain of patients appears to be an emerging potential therapeutic approach to neurodegenerative disease, such as Alzheimer's disease (AD). The intranasal route of administration could provide an alternative to intracere-broventricular infusion and gene therapy. We previously showed that intranasal administration of NGF determined an amelioration of cholinergic deficit and a decrease in the number of phosphotau-positive neurons and of beta-amyloid accumulation in AD11 mice, which express transgenic antibodies neutralizing NGF action and exhibit a progressive Alzheimer-like neurodegeneration. In this study, we report that the Alzheimer-like neurodegeneration in AD11 mice is linked to progressive behavioral deficits in visual recognition memory and spatial memory starting from 4 months of age. To establish whether intranasal administration of NGF, started after the appearance of the first memory deficits, could revert the cognitive deficits in AD11 mice, we assessed the performance of NGF-treated or control AD11 mice in the object recognition test and in a test of memory for place and context. Deficits exhibited by untreated AD11 mice could be rescued by the intranasal administration of NGF. Thus, this route of administration provides a promising way to deliver NGF to the brain in a therapeutic perspective.