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The LXR agonist TO901317 selectively lowers hippocampal Abeta42 and improves memory in the Tg2576 mouse model of Alzheimer's disease


Year of Publication:
Contact PI Name:
David R. Riddell
Contact PI Affiliation:
Discovery Neuroscience, Wyeth Research, Princeton, New Jersey, USA
Hua Zhou, Thomas A. Comery, Evguenia Kouranova, C. Frederick Lo, Helen K. Warwick, Robert H. Ring, Yolanda Kirksey, Suzan Aschmies, Jane Xu, Katie Kubek, Warren D. Hirst, Catherine Gonzales, Yi Chen, Erin Murphy, Sarah Leonard, Peter H. Reinhart, Jacobsen
Primary Reference (PubMED ID):
Funding Source:
Not Reported
Study Goal and Principal Findings:

Recent studies show that intracellular cholesterol levels can modulate the processing of amyloid precursor protein to Abeta peptide. Moreover, cholesterol-rich apoE-containing lipoproteins may also promote Abeta clearance. Agonists of the liver X receptor (LXR) transcriptionally induce genes involved in intracellular lipid efflux and transport, including apoE. Thus, LXR agonists have the potential to both inhibit APP processing and promote Abeta clearance. Here we show that LXR agonist, TO901317, increased hippocampal ABCA1 and apoE and decreased Abeta42 levels in APP transgenic mice. TO901317 had no significant effects on levels of Abeta40, full length APP, or the APP processing products. Next, we examined the effects of TO901317 in the contextual fear conditioning paradigm; TO901317 completely reversed the contextual memory deficit in these mice. These data demonstrate that LXR agonists do not directly inhibit APP processing but rather facilitate the clearance of Abeta42 and may represent a novel therapeutic approach to Alzheimer's disease.

Therapeutic Agent

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

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:

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
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


Outcome Measured
Outcome Parameters
Contextual Fear Conditioning
Amyloid Precursor Protein (APP)
Apolipoprotein E (ApoE)
ATP Binding Cassette Subfamily A Member 1 (ABCA1)
Liver X Receptor alpha (LXR alpha) mRNA
Liver X Receptor beta (LXR beta) mRNA
Brain-beta Amyloid Peptide 42
Brain-beta Amyloid Peptide 40
Soluble Amyloid Precursor Protein beta (sAPP beta)
Soluble Amyloid Precursor Protein alpha (sAPP alpha)
APP-CTF99 (CTF beta)
Brain-Guanidine Soluble beta Amyloid Peptide 40
Brain-Guanidine Soluble beta Amyloid Peptide 42
Plasma-beta Amyloid Peptide 40
Plasma-beta Amyloid Peptide 42
Target Engagement (Increased Liver X Receptor)