RESUMEN
The function of the amyloid precursor protein (APP), a key molecule in Alzheimer's disease (AD) remains unknown. Among the proteins that interact with the APP cytoplasmic domain in vitro and in heterologous systems is Disabled-1, a signaling molecule of the reelin pathway. The physiological consequence of this interaction is unknown. Here we used an in vitro model of hippocampal neurons grown on a reelin substrate that inhibits neurite outgrowth. Our results show that an excess of APP cytoplasmic domain internalized by a cell permeable peptide, is able to antagonize the neurite outgrowth inhibition of reelin. The APP cytoplasmic domain binds Disabled-1 and retains it in the cytoplasm, preventing it from reaching the plasma membrane and sequesters tyrosine phosphorylated Disabled-1, both of which disrupt reelin signaling. In the context of AD, increased formation of APP cytoplasmic domain in the cytosol released after cleavage of the A beta peptide, could then inhibit reelin signaling pathway in the hippocampus and thus influence synaptic plasticity.
Asunto(s)
Precursor de Proteína beta-Amiloide/fisiología , Moléculas de Adhesión Celular Neuronal/antagonistas & inhibidores , Moléculas de Adhesión Celular Neuronal/fisiología , Citoplasma/fisiología , Proteínas de la Matriz Extracelular/antagonistas & inhibidores , Proteínas de la Matriz Extracelular/fisiología , Hipocampo/crecimiento & desarrollo , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/fisiología , Neuritas/fisiología , Serina Endopeptidasas/fisiología , Secuencia de Aminoácidos , Precursor de Proteína beta-Amiloide/química , Animales , Células COS , Permeabilidad de la Membrana Celular/fisiología , Células Cultivadas , Chlorocebus aethiops , Citoplasma/química , Ratones , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/metabolismo , Inhibición Neural/fisiología , Neuronas/fisiología , Estructura Terciaria de Proteína/fisiología , Ratas , Proteína ReelinaRESUMEN
Schizophrenia is thought to be associated with abnormalities during neurodevelopment although those disturbances usually remain silent until puberty; suggesting that postnatal brain maturation precipitates the emergence of psychosis. In an attempt to model neurodevelopmental defects in the rat, brain cellular proliferation was briefly interrupted with methylazoxymethanol (MAM) during late gestation at embryonic day 17 (E17). The litters were explored at pre- and post-puberty and compared with E17 saline-injected rats. We measured spontaneous and provoked locomotion, working memory test, social interaction, and prepulse inhibition (PPI). As compared with the saline-exposed rats, the E17 MAM-exposed rats exhibited spontaneous hyperactivity that emerged only after puberty. At adulthood, they also exhibited hypersensitivity to the locomotor activating effects of a mild stress and a glutamatergic N-methyl-D-aspartate receptor antagonist (MK-801), as well as PPI deficits whereas before puberty no perturbations were observed. In addition, spatial working memory did not undergo the normal peri-pubertal maturation seen in the sham rats. Social interaction deficits were observed in MAM rats, at both pre- and post-puberty. Our study further confirms that transient prenatal disruption of neurogenesis by MAM at E17 is a valid behavioral model for schizophrenia as it is able to reproduce some fundamental features of schizophrenia with respect to both phenomenology and temporal pattern of the onset of symptoms and deficits.