RESUMEN

Alzheimer's disease (AD) is associated with impaired clearance of ß-amyloid (Aß) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator-activated receptor gamma and liver X receptors in coordination with retinoid X receptors (RXRs). Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble Aß within hours in an apoE-dependent manner. Aß plaque area was reduced more than 50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, RXR activation stimulates physiological Aß clearance mechanisms, resulting in the rapid reversal of a broad range of Aß-induced deficits.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Apolipoproteínas E/metabolismo , Encéfalo/metabolismo , Tetrahidronaftalenos/farmacología , Tetrahidronaftalenos/uso terapéutico , Amiloidosis/tratamiento farmacológico , Amiloidosis/metabolismo , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Conducta Animal/efectos de los fármacos , Bexaroteno , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Líquido Extracelular/efectos de los fármacos , Líquido Extracelular/metabolismo , Receptores X del Hígado , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/efectos de los fármacos , Microglía/metabolismo , Terapia Molecular Dirigida , Odorantes , Vías Olfatorias/efectos de los fármacos , Vías Olfatorias/fisiología , Receptores Nucleares Huérfanos/metabolismo , PPAR gamma/metabolismo , Fagocitosis , Placa Amiloide/tratamiento farmacológico , Receptores X Retinoide/agonistas , Receptores X Retinoide/metabolismo