RESUMO
Alzheimer's disease (AD) is characterized by neurodegeneration, memory loss, and social withdrawal. Brain inflammation has emerged as a key pathogenic mechanism in AD. We hypothesized that oxytocin, a pro-social hypothalamic neuropeptide with anti-inflammatory properties, could have therapeutic actions in AD. Here, we investigated oxytocin expression in experimental models of AD, and evaluated the therapeutic potential of treatment with oxytocin. Amyloid-ß peptide oligomers (AßOs) reduced oxytocin expression in vitro and in vivo, and treatment with oxytocin prevented microglial activation induced by AßOs in purified microglial cultures. Treatment of aged APP/PS1 mice, a mouse model of AD, with intranasal oxytocin attenuated microglial activation and favored deposition of Aß in dense core plaques, a potentially neuroprotective mechanism. Remarkably, treatment with oxytocin alleviated social and non-social memory impairments in aged APP/PS1 mice. Our findings point to oxytocin as a potential therapeutic target to reduce brain inflammation and correct memory deficits in AD.
RESUMO
Alzheimer's disease (AD) is the main cause of dementia in the elderly. Although activation of brain insulin signaling has been shown to be neuroprotective, to preserve memory in AD models, and appears beneficial in patients, the role of insulin-like growth factor 1 (IGF1) remains incompletely understood. We found reduced active/inactive IGF1 ratio and increased IGF1R expression in postmortem hippocampal tissue from AD patients, suggesting impaired brain IGF1 signaling in AD. Active/inactive IGF-1 ratio was also reduced in the brains of mouse models of AD. We next investigated the possible protective role of IGF1 in AD models. We used a recombinant adenoviral vector, RAd-IGF1, to drive the expression of IGF1 in primary hippocampal neuronal cultures prior to exposure to AßOs, toxins that accumulate in AD brains and have been implicated in early synapse dysfunction and memory impairment. Cultures transduced with RAd-IGF1 showed decreased binding of AßOs to neurons and were protected against AßO-induced neuronal oxidative stress and loss of dendritic spines. Significantly, in vivo transduction with RAd-IGF1 blocked memory impairment caused by intracerebroventricular (i.c.v.) infusion of AßOs in mice. Our results demonstrate altered active IGF1 and IGF1R levels in AD hippocampi, and suggest that boosting brain expression of IGF1 may comprise an approach to prevent neuronal damage and memory loss in AD.
Assuntos
Adenoviridae/patogenicidade , Doença de Alzheimer/metabolismo , Hipocampo/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Transtornos da Memória/prevenção & controle , Adenoviridae/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/virologia , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Memória/fisiologia , Transtornos da Memória/metabolismo , Camundongos , Neurônios/metabolismo , Sinapses/metabolismoRESUMO
BACKGROUND: Slice cultures have been prepared from several organs. With respect to the brain, advantages of slice cultures over dissociated cell cultures include maintenance of the cytoarchitecture and neuronal connectivity. Slice cultures from adult human brain have been reported and constitute a promising method to study neurological diseases. Despite this potential, few studies have characterized in detail cell survival and function along time in short-term, free-floating cultures. NEW METHOD: We used tissue from adult human brain cortex from patients undergoing temporal lobectomy to prepare 200 µm-thick slices. Along the period in culture, we evaluated neuronal survival, histological modifications, and neurotransmitter release. The toxicity of Alzheimer's-associated Aß oligomers (AßOs) to cultured slices was also analyzed. RESULTS: Neurons in human brain slices remain viable and neurochemically active for at least four days in vitro, which allowed detection of binding of AßOs. We further found that slices exposed to AßOs presented elevated levels of hyperphosphorylated Tau, a hallmark of Alzheimer's disease. COMPARISON WITH EXISTING METHOD(S): Although slice cultures from adult human brain have been previously prepared, this is the first report to analyze cell viability and neuronal activity in short-term free-floating cultures as a function of days in vitro. CONCLUSIONS: Once surgical tissue is available, the current protocol is easy to perform and produces functional slices from adult human brain. These slice cultures may represent a preferred model for translational studies of neurodegenerative disorders when long term culturing in not required, as in investigations on AßO neurotoxicity.