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

Zelcer, Noam; Khanlou, Négar; Clare, Ryan; Jiang, Qingguang; Reed-Geaghan, Erin G.; Landreth, Gary E.; Vinters, Harry V.; Tontonoz, Peter

doi:10.1073/pnas.0701096104

Cited by 305 publications

(243 citation statements)

References 66 publications

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“…This result agrees with findings in the literature of the contribution of lipid metabolism through liver X receptors (LXR) to the initiation and progression of this disease 52, 53…”

Section: Discussionsupporting

confidence: 93%

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

Gagliano

Pouget

Hardy

et al. 2016

Ann Clin Transl Neurol

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ObjectivesWe assessed the current genetic evidence for the involvement of various cell types and tissue types in the etiology of neurodegenerative diseases, especially in relation to the neuroinflammatory hypothesis of neurodegenerative diseases.MethodsWe obtained large‐scale genome‐wide association study (GWAS) summary statistics from Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). We used multiple sclerosis (MS), an autoimmune disease of the central nervous system, as a positive control. We applied stratified LD score regression to determine if functional marks for cell type and tissue activity, and gene‐set lists were enriched for genetic heritability. We compared our results to those from two gene‐set enrichment methods (Ingenuity Pathway Analysis and enrichr).ResultsThere were no significant heritability enrichments for annotations marking genes active within brain regions, but there were significant heritability enrichments for annotations marking genes active within cell types that form part of both the innate and adaptive immune systems. We found this for MS (as expected) and also for AD and PD. The strongest signals were from the adaptive immune system (e.g., T cells) for PD, and from both the adaptive (e.g., T cells) and innate (e.g., CD14: a marker for monocytes, and CD15: a marker for neutrophils) immune systems for AD. Annotations from the liver were also significant for AD. Pathway analysis provided complementary results.InterpretationFor AD and PD, we found significant enrichment of heritability in annotations marking gene activity in immune cells.

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“…This result agrees with findings in the literature of the contribution of lipid metabolism through liver X receptors (LXR) to the initiation and progression of this disease 52, 53…”

Section: Discussionsupporting

confidence: 93%

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

Gagliano

Pouget

Hardy

et al. 2016

Ann Clin Transl Neurol

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“…Inhibition of glial activation and reduction of glial-induced neurotoxicity by GW3965 appear to have prevented the loss of dopaminergic neurons in the PD mouse model. The present study is in line with a study by Zelcer et al (42) showing that an LXR agonist inhibits the inflammation response of primary glial cell and increases phagocytic capacity to fibrillar Aβ peptide in the setting of Alzheimer's disease in vitro.…”

Section: Discussionsupporting

confidence: 81%

Liver X receptor β protects dopaminergic neurons in a mouse model of Parkinson disease

Dai

Tan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Parkinson disease (PD) is a progressive neurodegenerative disease whose progression may be slowed, but at present there is no pharmacological intervention that would stop or reverse the disease. Liver X receptor β (LXRβ) is a member of the nuclear receptor super gene family expressed in the central nervous system, where it is important for cortical layering during development and survival of dopaminergic neurons throughout life. In the present study we have used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to investigate the possible use of LXRβ as a target for prevention or treatment of PD. The dopaminergic neurons of the substantia nigra of LXRβ −/− mice were much more severely affected by MPTP than were those of their WT littermates. In addition, the number of activated microglia and GFAPpositive astrocytes was higher in the substantia nigra of LXRβ −/− mice than in WT littermates. Administration of the LXR agonist GW3965 to MPTP-treated WT mice protected against loss of dopaminergic neurons and of dopaminergic fibers projecting to the striatum, and resulted in fewer activated microglia and astroglia. Surprisingly, LXRβ was not expressed in the neurons of the substantia nigra but in the microglia and astroglia. We conclude that LXR agonists may have beneficial effects in treatment of PD by modulating the cytotoxic functions of microglia.midbrain | neurodegeneration | neuroinflammation P arkinson disease (PD) is a common neurodegenerative disorder whose clinical features include tremor, slowness of movement, stiffness, and postural instability (1). PD is characterized by microgliosis, astrogliosis, progressive degeneration of dopaminergic neurons, presence of Lewy bodies in dopaminergic neurons, and α-synuclein accumulation in substantia nigra pars compacta (2). Although there are drugs that alleviate symptoms of PD, chronic use of these drugs results in debilitating side effects (3), and none seems to halt the progression of the disease. The etiology of PD remains unknown, but environmental toxins, genetic factors, and mitochondrial dysfunction are thought to be involved. Neuroinflammation (microglial activation, astrogliosis, and lymphocyte infiltration) results in production of cytotoxic molecules (4-9) that are directly involved in neuronal degeneration. It is now recognized that targeting neuroinflammation is one intervention that can slow down the progression of PD (10).1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that targets rather specifically dopaminergic neurons that are involved in PD; its administration leads to severe and irreversible PD-like syndrome in humans and nonhuman primates, with most of the biochemical and pathological hallmarks of PD (11), i.e., marked loss of dopaminergic neurons, astrogliosis, and activated microglia in the substantia nigra pars compacta (12). In 2002, Wu et al. (13) showed that dopaminergic neurons in the substantia nigra could be protected from MPTP-induced damage by the tetracycline derivative minocycline. This capaci...

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“…They suggest that this is a mechanism for removal and redistribution of cholesterol, which would be of benefit in neurodegenerative diseases associated with cholesterol accumulation in neurons. Similarly, Zelcer et al (39) have suggested that LXRs may be targets in treatment of Alzheimer's disease because of their ability to modulate both lipid metabolism and inflammatory gene expression.…”

Section: Discussionmentioning

confidence: 99%

Liver X receptor β (LXRβ): A link between β-sitosterol and amyotrophic lateral sclerosis–Parkinson's dementia

Kim¹,

Fan²,

Gabbi³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

129

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Administration of ␤-sitosterol (42 mg/kg per day) for 3 weeks to 8-month-old male LXR␤ ؊/؊ mice resulted in the death of motor neurons in the lumbar region of the spinal cord and loss of tyrosine hydroxylase-positive dopaminergic neurons in the substantia nigra. In mice at 5 months of age, ␤-sitosterol had no observed toxicity but at 16 months of age, it caused severe paralysis and symptoms typical of dopaminergic dysfunction in LXR␤ ؊/؊ mice. WT mice were not affected by these doses of ␤-sitosterol. In 5-month-old mice, levels of the intestinal transporters, ABCG5/8 and Niemann-Pick C1 Like 1, were not affected by loss of liver X receptor (LXR) ␤ and/or treatment with ␤-sitosterol nor were there changes in plasma levels of cholesterol or ␤-sitosterol. In 8-monthold LXR␤ ؊/؊ mice there was activation of microglia in the substantia nigra pars reticulata and aggregates of ubiquitin and TDP-43 in the cytoplasm of large motor neurons in the lumbar spinal cord. Brain cholesterol concentrations were higher in LXR␤ ؊/؊ than in their WT counterparts, and treatment with ␤-sitosterol reduced brain cholesterol in both WT and LXR␤ ؊/؊ mice. In LXR␤ ؊/؊ mice but not in WT mice levels of 24-hydrocholesterol were increased upon ␤-sitosterol treatment. These data indicate that multiple mechanisms are involved in the sensitivity of LXR␤ ؊/؊ mice to ␤-sitosterol. These include activation of microglia, accumulation of protein aggregates in the cytoplasm of large motor neurons, and depletion of brain cholesterol.central nervous system ͉ cholesterol ͉ microglia ͉ neurodegenerative disease ͉ nuclear receptor

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

Cited by 305 publications

References 66 publications

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

Liver X receptor β protects dopaminergic neurons in a mouse model of Parkinson disease

Liver X receptor β (LXRβ): A link between β-sitosterol and amyotrophic lateral sclerosis–Parkinson's dementia

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