Role of Liver X Receptor in AD Pathophysiology

Alzheimer's disease (AD) is the major cause of dementia worldwide. The pharmacological activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR) has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1) and Apolipoprotein E (ApoE), changes that are associated with improvement in cognition and reduction of amyloid beta pathology in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD). Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-months-old; three months treatment). The data suggests that the LXR agonist GW3965 is associated with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable reduction of the amyloid load. We also report that most cells overexpressing ApoE (86±12%) are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus. Additionally, we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD.

• Autores: Cardona Gómez, Gloria Patricia; Sandoval Hernández, Adrián G.; Buitrago, Luna; Moreno, Herman; Arboleda Bustos, Gonzalo
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2015
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/47824
• Acceso en línea: https://hdl.handle.net/10495/47824
• Palabra clave: 610 - Medicina y salud; Transportador 1 de Casete de Unión a ATP; ATP Binding Cassette Transporter 1; Alzheimer Disease; Enfermedad de Alzheimer; Péptidos beta-Amiloides; Amyloid beta-Peptides; Apolipoproteínas E; Apolipoproteins E; Benzoatos; Benzoates; Bencilaminas; Benzylamines; Corteza Cerebral; Cerebral Cortex; Trastornos del Conocimiento; Cognition Disorders; Proteínas de Unión al ADN; DNA-Binding Proteins; Giro Dentado; Dentate Gyrus; Hipocampo; Hippocampus; Receptores X del Hígado; Liver X Receptors; https://id.nlm.nih.gov/mesh/D064286; https://id.nlm.nih.gov/mesh/D000544; https://id.nlm.nih.gov/mesh/D016229; https://id.nlm.nih.gov/mesh/D001057; https://id.nlm.nih.gov/mesh/D001565; https://id.nlm.nih.gov/mesh/D001596; https://id.nlm.nih.gov/mesh/D002540; https://id.nlm.nih.gov/mesh/D003072; https://id.nlm.nih.gov/mesh/D004268; https://id.nlm.nih.gov/mesh/D018891; https://id.nlm.nih.gov/mesh/D006624; https://id.nlm.nih.gov/mesh/D000071518; ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades
• Rights: openAccess
• License: http://creativecommons.org/licenses/by/4.0/