Asunto(s)
Respiración Artificial/normas , Síndrome de Dificultad Respiratoria/prevención & control , Lesión Pulmonar Inducida por Ventilación Mecánica/prevención & control , Adulto , Anciano , Estudios de Casos y Controles , Servicio de Urgencia en Hospital/normas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Respiración Artificial/efectos adversos , Respiración Artificial/métodos , Terapia Respiratoria/educación , Terapia Respiratoria/normas , Estudios Retrospectivos , Volumen de Ventilación PulmonarRESUMEN
The canonical pathogenesis of Alzheimer's disease links the expression of apolipoprotein E ε4 allele (ApoE) to amyloid precursor protein (APP) processing and Aß peptide accumulation by a set of mechanisms that is incompletely defined. The development of a simple system that focuses not on a single variable but on multiple factors and pathways would be valuable both for dissecting the underlying mechanisms and for identifying candidate therapeutics. Here we show that, although both ApoE3 and ApoE4 associate with APP with nanomolar affinities, only ApoE4 significantly (i) reduces the ratio of soluble amyloid precursor protein alpha (sAPPα) to Aß; (ii) reduces Sirtuin T1 (SirT1) expression, resulting in markedly differing ratios of neuroprotective SirT1 to neurotoxic SirT2; (iii) triggers Tau phosphorylation and APP phosphorylation; and (iv) induces programmed cell death. We describe a subset of drug candidates that interferes with the APP-ApoE interaction and returns the parameters noted above to normal. Our data support the hypothesis that neuronal connectivity, as reflected in the ratios of critical mediators such as sAPPα:Aß, SirT1:SirT2, APP:phosphorylated (p)-APP, and Tau:p-Tau, is programmatically altered by ApoE4 and offer a simple system for the identification of program mediators and therapeutic candidates.