title: Role of Liver X Receptor in AD Pathophysiology.
abstract: 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.
authors.affiliation: Grupo de Muerte Celular, Instituto de Genética Universidad Nacional de Colombia, Bogotá, Colombia.
authors.forename: Adrián G
authors.initials: AG
authors.lastname: Sandoval-Hernández
authors.affiliation: Departments of Neurology and Physiology/Pharmacology, The Robert F. Furchgott Center for Neural and Behavioral Science, SUNY Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: Luna
authors.initials: L
authors.lastname: Buitrago
authors.affiliation: Departments of Neurology and Physiology/Pharmacology, The Robert F. Furchgott Center for Neural and Behavioral Science, SUNY Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: Herman
authors.initials: H
authors.lastname: Moreno
authors.affiliation: Área de Neurobiología Celular y Molecular, Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Calle 70, No. 52-21, Medellín, Colombia.
authors.forename: Gloria Patricia
authors.initials: GP
authors.lastname: Cardona-Gómez
authors.affiliation: Grupo de Muerte Celular, Instituto de Genética Universidad Nacional de Colombia, Bogotá, Colombia.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Arboleda
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use; D001596:Benzylamines / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D004268:DNA-Binding Proteins; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D005455:Fluorescent Antibody Technique; D005911:Gliosis / Q000150:complications / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D001565:Benzoates; D001596:Benzylamines; D015415:Biomarkers; D004268:DNA-Binding Proteins; C473027:GW 3965; D000071518:Liver X Receptors; D009419:Nerve Tissue Proteins; D064231:Nestin; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D016875:tau Proteins