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

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 en...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 25; p. 10601
Main Authors: Zelcer, Noam, Khanlou, Negar, Clare, Ryan, Jiang, Qingguang, Reed-Geaghan, Erin G, Landreth, Gary E, Vinters, Harry V, Tontonoz, Peter
Format: Journal Article
Language:English
Published: United States 19.06.2007
Subjects:
Alzheimer Disease - pathology
Amyloid beta-Peptides - pharmacology
Animals
Brain - metabolism
Brain - pathology
Cells, Cultured
Cholesterol - genetics
Cholesterol - metabolism
DNA-Binding Proteins - genetics
DNA-Binding Proteins - physiology
Fluorescent Antibody Technique, Indirect
Gene Expression Regulation - physiology
Immunohistochemistry
Inflammation - metabolism
Inflammation - pathology
Lipid Metabolism
Liver X Receptors
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Microglia - cytology
Microglia - drug effects
Microglia - physiology
Orphan Nuclear Receptors
Phagocytosis - drug effects
Phagocytosis - physiology
Plaque, Amyloid - pathology
Receptors, Cytoplasmic and Nuclear - genetics
Receptors, Cytoplasmic and Nuclear - physiology
Signal Transduction
ISSN:0027-8424
Online Access:Get more information
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Summary: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 Lxralpha or Lxrbeta 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 beta peptide (fAbeta) in a receptor-dependent manner. Furthermore, LXRs promote the capacity of microglia to maintain fAbeta-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.
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ISSN:0027-8424
DOI:10.1073/pnas.0701096104