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

Fritz, Nicholas F. and Cronican, Andreas and Pham, Tam and Fogg, Allison and Lefterov, Iliya and Koldamova, Radosveta (2010) LXR agonist treatment ameliorates amyloid pathology and memory deficits caused by high fat diet in APP23 mice. The Journal of Neuroscience, 30 (20). pp. 6862-6872.

Abstract

High fat diet feeding is associated with higher incidence of Alzheimer’s disease (AD) and cognitive decline.
However, no specific therapy has been suggested to ameliorate the negative effects of 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 in both acquisition and retention phases of the Morris Water
Maze. Moreover, the effects of T0 on cognition correlated 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 from LXRα/β and Abca1 knockout mice support
the hypothesis that Aβ degradation by microglia depends on the presence of functional LXR
and Abca1. Results from these experiments demonstrate that Abca1 is essential for the proper lipidation
of ApoE and mediates the effects of LXR on Aβ degradation by microglia. The data presented
here conclusively show that LXR activation in the context of a metabolic challenge has critical
effects on the progression of the AD phenotype by attenuating Aβ deposition and clearance.

Item Type: Article
Related URLs:
Keywords: LXR, high fat diet, Aβ, behavior, ABCA1, ApoE, APP23
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2179

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