Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high fat diet in APP23 mice


BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2010
Contact PI Name:
Radosveta Koldamova
Contact PI Affiliation:
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Co-Authors:
Nicholas F. Fitz, Andrea Cronican, Tam Pham, Allison Fogg, Abdul H. Fauq, Robert Chapman, Iliya Lefterov
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Alzheimer's Association
Alzheimer's Art Quilt Initiative
Study Goal and Principal Findings:

High fat diet and certain dietary patterns are associated with higher incidence of sporadic Alzheimer’s disease (AD) and cognitive decline. However, no specific therapy has been suggested to ameliorate the negative effects of high fat/high cholesterol levels on cognition and amyloid pathology. Here we show that in 9 month old APP23 mice, a high fat/high cholesterol (HF) diet provided for 4 months exacerbates the AD phenotype evaluated by behavioral, morphological and biochemical assays. To examine the therapeutic potential of Liver X Receptor (LXR) ligands, APP23 mice were fed HF diet supplemented with synthetic LXR agonist T0901317 (T0). Our results demonstrate that LXR ligand treatment causes a significant reduction of memory deficits observed during both acquisition and retention phases of the Morris Water Maze. Moreover, the effects of T0 on cognition correlate with AD-like morphological and biochemical parameters. We found a significant decrease in amyloid plaque load, insoluble Aβ and soluble Aβ oligomers. In vitro experiments with primary glia demonstrated that Abca1 is essential for the proper lipidation of ApoE and mediates the effects of T0 on Aβ degradation by microglia. Microdialysis experiments performed on awake freely moving mice showed that T0 decreased Aβ level in the interstitial fluid of the hippocampus, supporting the conclusion that this treatment increases Aβ clearance. The data presented conclusively shows that LXR activation in the context of a metabolic challenge has critical effects on AD phenotype progression by attenuating Aβ deposition and facilitating its clearance.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
T0901317
Therapeutic Target:
Liver X Receptors

Animal Model

Model Information:
Species:
Mouse
Model Type:
APP
Strain/Genetic Background:
C57BL/6
Species:
Mouse
Model Type:
Non-transgenic
Strain/Genetic Background:
C57B16

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest

Outcomes

Outcome Measured
Outcome Parameters
Behavioral
Morris Water Maze
Histopathology
beta Amyloid Load
Biochemical
ISF-beta Amyloid Peptide 40
ISF-beta Amyloid Peptide 42
Brain-Formic Acid Insoluble beta Amyloid Peptide 40
Brain-Formic Acid Insoluble beta Amyloid Peptide 42
Brain-Formic Acid Soluble beta Amyloid Peptide 40
Brain-Formic Acid Soluble beta Amyloid Peptide 42
Amyloid Precursor Protein (APP) Metabolites
Amyloid Precursor Protein (APP)
Brain-Detergent Soluble beta Amyloid Peptide 40
Brain-Detergent Soluble beta Amyloid Peptide 42
Brain-Detergent Insoluble beta Amyloid Peptide 40
Brain-Detergent Insoluble beta Amyloid Peptide 42
Brain-beta Amyloid Oligomers
Apolipoprotein E-Containing Lipoproteins
Apolipoprotein E (ApoE)
ATP Binding Cassette Subfamily A Member 1 (ABCA1)
Cell Biology
beta Amyloid Peptide Degradation

Source URL: http://alzped.nia.nih.gov/liver-x-receptor-agonist