RESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder, marked by senile plaques composed of amyloid-ß (Aß) peptide, neurofibrillary tangles, neuronal loss and neuroinflammation. Previous works have suggested that systemic inflammation could contribute to neuroinflammation and enhanced Aß cerebral concentrations. The molecular pathways leading to these events are not fully understood. PKR is a pro-apoptotic kinase that can trigger inflammation and accumulates in the brain and cerebrospinal fluid of AD patients. The goal of the present study was to assess if LPS-induced neuroinflammation and Aß production could be altered by genetic PKR down regulation. The results show that, in the hippocampus of LPS-injected wild type mice, neuroinflammation, cytokine release and Aß production are significantly increased and not in LPS-treated PKR knock-out mice. In addition BACE1 and activated STAT3 levels, a putative transcriptional regulator of BACE1, were not found increased in the brain of PKR knock-out mice as observed in wild type mice. Using PET imaging, the decrease of hippocampal metabolism induced by systemic LPS was not observed in LPS-treated PKR knock-out mice. Altogether, these findings demonstrate that PKR plays a major role in brain changes induced by LPS and could be a valid target to modulate neuroinflammation and Aß production.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Regulação da Expressão Gênica , Inflamação/genética , Inflamação/metabolismo , eIF-2 Quinase/genética , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Citocinas/biossíntese , Modelos Animais de Doenças , Regulação para Baixo , Ativação Enzimática , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação/diagnóstico , Inflamação/patologia , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/efeitos adversos , Imageamento por Ressonância Magnética , Camundongos , Camundongos Knockout , Microglia/imunologia , Microglia/metabolismo , Fosforilação , Tomografia por Emissão de Pósitrons , Fator de Transcrição STAT3/metabolismo , eIF-2 Quinase/antagonistas & inibidores , eIF-2 Quinase/metabolismoRESUMO
BACKGROUND: The control of translation, involving the kinases mTOR (mammalian target of rapamycin) and PKR (double-stranded RNA-dependent protein kinase), modulates cell survival and death and is altered in the brains of patients with Alzheimer's disease (AD). In AD increased susceptibility of lymphocytes to apoptosis has been reported. METHODS: We investigated the level of the kinases mTOR and PKR and the eukaryotic initiation factor 2alpha (eIF2alpha) in lymphocytes of patients with AD in comparison with controls. In AD patients we also looked for a correlation between activated proteins and cognitive and memory tests. RESULTS: We report significant alterations of the levels of these kinases and eIF2alpha in lymphocytes of AD patients that were also significantly correlated with cognitive and memory test scores. CONCLUSION: These results suggest that the levels of mTOR, PKR and eIF2alpha in lymphocytes could follow the cognitive decline in AD.
