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PMID: 17563384 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 104 ·No. 25 ·2007-06-19 ·Pages 10601-6

Zelcer N, Khanlou N, Clare R, Jiang Q, Reed-Geaghan EG, Landreth GE, Vinters HV, Tontonoz P

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 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.

MeSH Terms
Alzheimer Disease/pathology Amyloid beta-Peptides/pharmacology Animals Brain/metabolism,pathology Cells, Cultured Cholesterol/genetics,metabolism DNA-Binding Proteins/genetics,physiology Fluorescent Antibody Technique, Indirect Gene Expression Regulation/physiology Immunohistochemistry Inflammation/metabolism,pathology Lipid Metabolism Liver X Receptors Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Microglia/cytology,drug effects,physiology Orphan Nuclear Receptors Phagocytosis/drug effects,physiology Plaque, Amyloid/pathology Receptors, Cytoplasmic and Nuclear/genetics,physiology Signal Transduction
Chemicals
Amyloid beta-Peptides DNA-Binding Proteins Liver X Receptors Nr1h3 protein, mouse Orphan Nuclear Receptors Receptors, Cytoplasmic and Nuclear Cholesterol
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Zelcer Noam
Department of Pathology, University of California, Los Angeles, CA 90095, USA.
Khanlou Negar
Clare Ryan
Jiang Qingguang
Reed-Geaghan Erin G
Landreth Gary E
Vinters Harry V
Tontonoz Peter
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0701096104
Published
2007-06-19
Epub
2007-00-11
Pages
10601-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1890560
Subset
IM
Grants
NHLBI NIH HHS · HL66088 · United States
NIA NIH HHS · P50 AG16570 · United States
NIA NIH HHS · P50 AG016570 · United States
Howard Hughes Medical Institute · United States
NHLBI NIH HHS · R01 HL066088 · United States
NHLBI NIH HHS · HL30568 · United States
NHLBI NIH HHS · P01 HL030568 · United States
External Links
PubMed source DOI: 10.1073/pnas.0701096104 PMC Full Text View journal details
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