PT  - JOURNAL ARTICLE
AU  - Nicholas F. Fitz
AU  - Andrea Cronican
AU  - Tam Pham
AU  - Allison Fogg
AU  - Abdul H. Fauq
AU  - Robert Chapman
AU  - Iliya Lefterov
AU  - Radosveta Koldamova
TI  - Liver X Receptor Agonist Treatment Ameliorates Amyloid Pathology and Memory Deficits Caused by High-Fat Diet in APP23 Mice
AID  - 10.1523/JNEUROSCI.1051-10.2010
DP  - 2010 May 19
TA  - The Journal of Neuroscience
PG  - 6862--6872
VI  - 30
IP  - 20
4099  - http://www.jneurosci.org/content/30/20/6862.short
4100  - http://www.jneurosci.org/content/30/20/6862.full
SO  - J. Neurosci.2010 May 19; 30
AB  - 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 demonstrate 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 levels 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.