RESUMO
The 5XFAD mice are an early-onset transgenic model of Alzheimer's disease (AD) in which amyloid plaques are first observed between two and four months of age in the cortical layer five and in the subiculum of the hippocampal formation. Although cognitive alterations have been described in these mice, there are no studies that focused on the onset of hippocampus-dependent memory deficits, which are a hallmark of the prodromal stage of AD. To identify when the first learning and memory impairments appear, 5XFAD mice of two, four, and six months of age were compared with their respective wild-type littermates using the olfactory tubing maze, which is a very sensitive hippocampal-dependent task. Deficits in learning and memory started at four months with a substantial increase at six months of age while no olfactory impairments were observed. The volumetric study using magnetic resonance imaging of the whole brain and specific areas (olfactory bulb, striatum, and hippocampus) did not reveal neuro-anatomical difference. Slight memory deficits appeared at 4 months of age in correlation with an increased astrogliosis and amyloid plaque formation. This early impairment in learning and memory related to the hippocampal dysfunction is particularly suited to assess preclinical therapeutic strategies aiming to delay or suppress the onset of AD.
Assuntos
Doença de Alzheimer/psicologia , Hipocampo/fisiopatologia , Deficiências da Aprendizagem/etiologia , Transtornos da Memória/etiologia , Idade de Início , Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/genética , Animais , Astrócitos/patologia , Corpo Estriado/patologia , Gliose/etiologia , Gliose/patologia , Hipocampo/patologia , Deficiências da Aprendizagem/patologia , Deficiências da Aprendizagem/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/patologia , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Transgênicos , Bulbo Olfatório/patologia , Tamanho do Órgão , Placa Amiloide/etiologia , Placa Amiloide/patologia , Mutação Puntual , Presenilina-1/genética , Olfato/fisiologiaRESUMO
The frontal cortex is a brain structure that plays an important role in cognition and is known to be affected in Alzheimer's disease (AD) in humans. Over the past years, transgenic mouse models have been generated to recapitulate the main features of this disease, including cognitive impairments. This study investigates frontal cortex dependent learning abilities in one of the most early-onset transgenic murine model of AD, the 5XFAD mice. We compared frontal performance of 2-, 4-, and 6-month-old 5XFAD mice with their wild-type littermates using a newly developed automated device, the olfactory H-maze, in which mice have to discover three different rules consecutively according to the delayed reaction paradigm. We report early cognitive deficits related to frontal cortex appearing in 4-month-old 5XFAD mice before hippocampal-dependent learning and memory impairment, in relation with neuropathologic processes such as strong gliosis and emerging amyloid plaques. The present results demonstrate that the olfactory H-maze is a very sensitive and simple experimental paradigm that allows assessment of frontal functions in transgenic mice and should be useful to test pre-clinical therapeutic approaches to alter the course of AD.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Lobo Frontal/patologia , Transtornos do Olfato/etiologia , Fatores Etários , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Animais , Disfunção Cognitiva/genética , Lobo Frontal/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Imageamento por Ressonância Magnética , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Transtornos do Olfato/genética , Presenilina-1/genética , Tempo de Reação/genéticaRESUMO
In normal aging, or pathological brain diseases in humans, implicit memory (or procedural memory in rats) is spared while explicit memory (or reference memory in rats) is deeply impaired. Selective activation of 5-HT(4) receptors by a partial 5-HT(4) receptor agonist (SL65.0155) improved memory performance in an olfactory associative discrimination task in aged rats. Detailed analysis of subcategories of long-term memory using a hippocampal-dependent olfactory associative discrimination task revealed a substantial benefit on reference memory. This agent could be used to treat early mnesic deficits observed in normal aging or in neurodegenerative disorders like Alzheimer disease.