Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors

Departments of *Pathology and Laboratory Medicine and
^‡Neurology and
^†Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095; and
^§Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106

Edited by Ronald M. Evans, The Salk Institute for Biological Studies, San Diego, CA, and approved May 17, 2007 (received for review February 6, 2007)

Abstract

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease that causes progressive cognitive impairment. The initiation and progression of AD has been linked to cholesterol metabolism and inflammation, processes that can be modulated by liver x receptors (LXRs). We show here that endogenous LXR signaling impacts the development of AD-related pathology. Genetic loss of either Lxrα or Lxrβ in APP/PS1 transgenic mice results in increased amyloid plaque load. LXRs regulate basal and inducible expression of key cholesterol homeostatic genes in the brain and act as potent inhibitors of inflammatory gene expression. Ligand activation of LXRs attenuates the inflammatory response of primary mixed glial cultures to fibrillar amyloid β peptide (fAβ) in a receptor-dependent manner. Furthermore, LXRs promote the capacity of microglia to maintain fAβ-stimulated phagocytosis in the setting of inflammation. These results identify endogenous LXR signaling as an important determinant of AD pathogenesis in mice. We propose that LXRs may be tractable targets for the treatment of AD due to their ability to modulate both lipid metabolic and inflammatory gene expression in the brain.

Footnotes

^¶To whom correspondence should be sent at:
Howard Hughes Medical Institute/University of California, Los Angeles, 675 Charles Young Drive, Los Angeles, CA 90095.
E-mail: ptontonoz{at}mednet.ucla.edu
Author contributions: N.Z., G.E.L., and P.T. designed research; N.Z., N.K., R.C., Q.J., E.G.R.-G., and H.V.V. performed research; N.Z., N.K., R.C., Q.J., E.G.R.-G., G.E.L., H.V.V., and P.T. analyzed data; and N.Z., G.E.L., H.V.V., and P.T. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0701096104/DC1.
Abbreviations:

ABCA1,

ATP-binding cassette A1;

Aβ,

amyloid β peptide;

AD,

Alzheimer disease;

apoN,

apolipoprotein N;

APP,

amyloid precursor protein;

fAβ,

fibrillar Aβ;

KO,

knockout;

LPS,

lipopolysaccharide(s);

LXR,

liver x receptor;

Tg,

transgenic.
Freely available online through the PNAS open access option.