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Cited by 358Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsCholesterol and Lipid Metabolism

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

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Zelcer, Noam, Khanlou, Negar, Clare, Ryan, Jiang, Qingguang, Reed-Geaghan, Erin G., Landreth, Gary E., Vinters, Harry V., Tontonoz, Peter·2007·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0701096104PMC PMC1890560
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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 Lxr α or Lxr β 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.

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  • LXR agonists decrease Aβ deposition in the brain while modestly increasing apoE expression.

    “LXR agonists have been shown to decrease A␤ deposition in the brain while modestly increasing apoE expression (Koldamova et al., 2005;Zelcer et al., 2007;Fitz et al., 2010).”

    From Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis (2014) · cites this paper as Zelcer et al., 2007

    The Results report that loss of LXR increased cortical Aβ plaques in APP/PS1 mice, but this is not a demonstration that agonist treatment decreased brain Aβ deposition. The Results also state that Apoe mRNA was not induced by LXR ligand treatment, contrary to the claimed increase in expression; Apoe protein was lower in LXR-null mice. Page numbers were not available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Activation of nuclear receptors suppresses NFκB-mediated inflammatory responses and activates phagocytic machinery.

    “Activation of these nuclear receptors suppresses NFκB-mediated inflammatory responses and activates their phagocytic machinery (Zelcer et al., 2007; Mukundan et al., 2009; Glass and Saijo, 2010).”

    From Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease (2012) · cites this paper as Zelcer et al., 2007

    The Results report that LXR activation suppresses inflammatory responses and restores fibrillar Aβ-stimulated phagocytosis in microglia when inflammation has inhibited it. The Discussion says this restoration occurs most likely through inhibition of NFκB activity. The claim overstates that proposed mechanism as established and describes restored phagocytosis as activation of phagocytic machinery. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Nuclear receptors play a crucial role in promoting the phenotypic change of macrophages from classically M1 activated to alternatively activated M2 states.

    “Nuclear receptors have only recently been appreciated to play an crucial role in promoting the phenotypic change of macrophages from a “classically” M1 activated to alternatively activated M2 states (Odegaard et al., 2007, 2008; Zelcer et al., 2007; Bouhlel et al., 2008; Kalinin et al., 2009; Chawla, 2010).”

    From Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease (2012) · cites this paper as Zelcer et al., 2007

    The Abstract says LXRs are nuclear receptors that inhibit inflammatory responses in macrophages, and the Results show that LXR activation suppresses inflammatory responses in microglia. Neither passage establishes the claimed phenotypic change of macrophages from M1 to M2 states. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • In vivo Aβ removal is critically dependent on microglial activation status.

    “However, considerable evidence suggests that in vivo A␤ removal is critically dependent on microglial activation status.33,44 -47”

    From CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models (2010) · cites this paper as [45]

    The Results (page not available) show that inflammatory signals suppress microglial phagocytosis of Aβ and that LXR treatment reverses this effect in cultured cells. The Discussion (page not available) proposes that this mechanism may affect amyloid clearance in the brain, while the in vivo finding is increased plaque burden in LXR-deficient mice. The paper does not establish that in vivo Aβ removal is critically dependent on microglial activation status. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Loss of LXRα or LXRβ increases Aβ plaque burden in APP/PS1 mouse.

    “We previously reported that loss of LXRα or LXRβ increases Aβ plaque burden in the APP/PS1 mouse (50).”

    From The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis (2015) · cites this paper as [50]

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References 68 · Cited by 358

Research works printed but not linked: 57

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Authors
Zelcer, N., Khanlou, N., Clare, R., Jiang, Q., Reed-Geaghan, E. G., Landreth, G. E., Vinters, H. V., & Tontonoz, P.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Departments of *Pathology and Laboratory Medicine and
  • University of California, Los Angeles (US)
  • Case Western Reserve University (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2007-06-19
Volume
104
Issue
25
Pages
10601-10606
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0701096104
PMC
PMC1890560
OpenAlex
W2128094952
Cited by
358
References
68
Citations by year
2026: 9 · 2025: 18 · 2024: 13 · 2023: 12 · 2022: 12 · 2021: 17 · 2020: 18 · 2019: 16 · 2018: 13 · 2017: 13 · 2016: 21 · 2015: 18 · 2014: 27 · 2013: 31 · 2012: 17
FWCI
17.89
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institute on Aging (P50AG016570, P50-AG 16570)
  • National Heart, Lung, and Blood Institute (HL3 0568, P01HL030568, R01HL066088, HL66088)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
Alzheimer's disease, liver X receptor, neuroinflammation, amyloid plaques, cholesterol metabolism, liver X receptor alpha, LXRβ, APP/PS1 mice, amyloid-beta, microglia, phagocytosis, glial inflammation, LXR ligands, lipid metabolism, gene expression regulation
MeSH terms
Liver X Receptors, Alzheimer Disease, Animals, Brain, Cells, Cultured, Cholesterol, DNA-Binding Proteins, Gene Expression Regulation, Immunohistochemistry, Inflammation, Mice, Inbred C57BL, Mice, Transgenic, Phagocytosis, Signal Transduction, Amyloid beta-Peptides, Microglia, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Fluorescent Antibody Technique, Indirect, Lipid Metabolism, Mice, Orphan Nuclear Receptors, Plaque, Amyloid

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