RESUMEN
Megalin has been suggested to be involved in Alzheimer's disease (AD), mediating blood-brain barrier (BBB) transport of multiple ligands, including amyloid-ß peptide (Aß), but also neuroprotective factors. Because no transgenic model is currently available to study this concept, we have obtained transgenic mice blocking megalin expression at the BBB. These endothelial megalin deficient (EMD) mice developed increased anxiety behavior and impaired learning ability and recognition memory, similar to symptoms described in AD. Degenerating neurons were also observed in the cerebral cortex of EMD mice. In view of our findings we suggest that, in mice, megalin deficiency at the BBB leads to neurodegeneration.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Trastornos del Conocimiento/metabolismo , Células Endoteliales/metabolismo , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/deficiencia , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Células Cultivadas , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/patología , Células Endoteliales/patología , Humanos , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Masculino , Ratones , Ratones Noqueados , Ratones TransgénicosRESUMEN
Leptin, a peptide hormone secreted by adipose tissue, exhibits a large range of central and peripheral actions. It has been proposed that the participation of leptin in diseases such as obesity is due to, at least in part, its impaired transport across the blood-brain barrier (BBB). Since, the mechanisms by which brain takes up leptin remain unclear, we set out to study how leptin may cross the BBB. We have used different immunoassays and lentiviral vectors to analyze the role of megalin in the transport of leptin in rodents and humans. We demonstrate that circulating leptin is transported into the brain by binding to megalin at the choroid plexus epithelium. Indeed, the downregulation of megalin expression in physiological and pathological situations such as aging and Alzheimer's disease was correlated with poor entry of leptin into the brain. Moreover, amyloid beta (Abeta) deposits of choroid plexus could be disturbing megalin function. The present data indicate that leptin represents a novel megalin ligand of importance in the levels and therapeutic actions of leptin into the brain.
Asunto(s)
Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Barrera Hematoencefálica/metabolismo , Líquido Cefalorraquídeo/metabolismo , Plexo Coroideo/metabolismo , Leptina/metabolismo , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Anciano , Animales , Transporte Biológico Activo/fisiología , Femenino , Humanos , Masculino , Ratas , Ratas Wistar , Transducción de SeñalRESUMEN
It is increasingly recognized that life-style factors, such as physical exercise or diet influence brain health. In the present work we analyzed the effect of a western-style diet ("cafeteria diet") on the entrance to the brain of circulating IGF-1, a neuroprotective agent that has been related to different neurodegenerative diseases. Rats under a cafeteria diet showed reduced passage of systemic IGF-1 across the choroid plexus, a main site of IGF-1 entrance into the brain through the cerebrospinal fluid. Furthermore, the IGF-1 receptor at the choroid plexus of rats fed with a cafeteria diet showed enhanced sensitivity toward IGF-1 while receptor levels remained unchanged. Examination of possible mechanisms underlying reduced entrance of systemic IGF-1 to the brain showed that triglycerides that increased in blood after a cafeteria diet, diminished the passage of IGF-1 across choroid plexus epithelia. This effect of triglycerides was achieved by altering the interaction of IGF-1 with megalin, a choroid plexus transporter involved in transcytosis of IGF-1 from the circulation into the brain. Reduced brain entrance of circulating IGF-1 elicited by a western-style diet suggests that the higher incidence of brain diseases related to inadequate diets is due in part to diminished neurotrophic support.