Role of Liver X Receptor in AD Pathophysiology

• Published in: PloS one 2015-12, Vol.10 (12), p.e0145467
• Main Authors: Sandoval-Hernández, Adrián G, Buitrago, Luna, Moreno, Herman, Cardona-Gómez, Gloria Patricia, Arboleda, Gonzalo
• Format: Article
• Language: English
• Subjects: ABCA1 protein; Advertising executives; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer's disease; Alzheimers disease; Amyloid beta-Peptides - metabolism; Amyloidogenesis; Animal cognition; Animal models; Animals; Apolipoprotein E; Apolipoproteins; Apolipoproteins E - metabolism; ATP Binding Cassette Transporter 1 - metabolism; ATP-binding protein; Behavioral sciences; Benzoates - pharmacology; Benzoates - therapeutic use; Benzylamines - pharmacology; Benzylamines - therapeutic use; Biomarkers - metabolism; Brain; Cell Proliferation - drug effects; Cerebral cortex; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Chemical synthesis; Cholesterol; Cognition; Cognition Disorders - complications; Cognition Disorders - drug therapy; Cognition Disorders - metabolism; Cognition Disorders - physiopathology; Cognitive ability; Cortex (entorhinal); Dementia disorders; Dentate gyrus; Dentate Gyrus - drug effects; Dentate Gyrus - metabolism; Dentate Gyrus - pathology; Excitatory Postsynaptic Potentials - drug effects; Female; Fluorescent Antibody Technique; Furchgott, Robert F; Gliosis; Gliosis - complications; Gliosis - pathology; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Kinases; Laboratory animals; Ligands; Lipids; Liver; Liver X Receptors; Long-Term Potentiation - drug effects; Male; Metabolism; Metabolites; Mice, Transgenic; Molecular modelling; Nerve Tissue Proteins - metabolism; Nestin - metabolism; Neural Stem Cells - drug effects; Neural Stem Cells - metabolism; Neurodegeneration; Neurodegenerative diseases; Neurogenesis; Neurons; Nuclear Proteins - metabolism; Nuclear receptors; Orphan Nuclear Receptors - agonists; Orphan Nuclear Receptors - metabolism; Peptides; Pharmacology; Physiology; Presenilin 1; Protein biosynthesis; Protein Biosynthesis - drug effects; Protein synthesis; Proteins; Receptors; Reduction; Retinoid X receptors; Rodents; Stem cells; Synaptic plasticity; Tau protein; tau Proteins - metabolism; Up-Regulation - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0145467

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.