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

Kim, Hyun Jin; Fan, Xiaotang; Gabbi, Chiara; Yakimchuk, Konstantin; Parini, Paolo; Warner, Margaret; Gustafsson, Jan Åke

doi:10.1073/pnas.0711599105

Cited by 125 publications

(89 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These observations suggest that LXRβ may be protective against neurodegeneration of substantia nigra (25). Furthermore, there is activation of microglia in the substantia nigra of aging LXRβ −/− mice, and this suggests that LXR may have immunosuppressive effects in the brain (26) as it does in the rest of the immune system. The present study demonstrates that LXRβ −/− mice treated with MPTP lost more TH-positive neurons in the substantia nigra and had more activated microglia and GFAP + astrocytes in this part of the brain.…”

Section: Discussionmentioning

confidence: 73%

“…We have previously shown that LXRβ expression is involved in formation of superficial cortical layers and migration of later-born neurons in embryonic mice (23,24), and that LXRβ is essential for maintenance of motor neurons in the spinal cord and dopaminergic neurons in the substantia nigra (25,26). The substantia nigra and motor neurons in the spinal cords of LXRβ −/− mice are normal until the mice are 6 mo of age.…”

mentioning

confidence: 99%

“…The substantia nigra and motor neurons in the spinal cords of LXRβ −/− mice are normal until the mice are 6 mo of age. After this, mice begin to perform poorly on a rotor rod, and lose the large motor neurons in the spinal cord and dopaminergic neurons in the substantia nigra (26). LXR agonists reduce inflammation by inhibiting the expression of inflammatory mediators such as inducible nitric oxide synthase, cyclooxygenase-2 and interleukin-6 in macrophages, microglia, and astrocytes (27,28).…”

mentioning

confidence: 99%

See 2 more Smart Citations

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.

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 73%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Primary antibodies were detected with donkey antigoat Cy3 (1:400; Jackson ImmunoResearch), donkey antirabbit FITC (1:400; Santa Cruz Biotechnology), donkey antichicken FITC (1:400; Jackson ImmunoResearch), and donkey antimouse Cy3 (1:400; Jackson ImmunoResearch). Sections were later counterstained with Vectashield mounting medium containing 4', 6'-diamidino-2-phenylindole (DAPI) (Vector) to label nuclei (43,44).…”

Section: Methodsmentioning

confidence: 99%

Reduction of dendritic spines and elevation of GABAergic signaling in the brains of mice treated with an estrogen receptor β ligand

Tan

Dai

et al. 2012

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

Self Cite

View full text Add to dashboard Cite

An estrogen receptor (ER) β ligand (LY3201) with a preference for ERβ over ERα was administered in s.c. pellets releasing 0.04 mg/d. The brains of these mice were examined 3 d after treatment had begun. Although estradiol-17β is known to increase spine density and glutaminergic signaling, as measured by Golgi staining, a clear reduction in spines was evident on the dendritic branches in LY3201-treated mice but no morphological alteration and no difference in the number of dendritic spines on dendritic stems were observed. In the LY3201-treatment group, there was higher expression of glutamic acid decarboxylase (GAD) in layer V of cortex and in the CA1 of hippocampus, more GAD + terminals surrounding the pyramidal neurons and less glutamate receptor (NMDAR) on the neurons in layer V. There were no alterations in expression of Iba1 or in Olig2 or CNPase. However, GFAP + astrocytes were increased in the LY3201-treatment group. There were also more projections characteristic of activated astrocytes and increased expression of glutamine synthetase (GS). No expression of ERβ was detectable in the nuclei of astrocytes. Clearly, LY3201 caused a shift in the balance between excitatory and inhibitory neurotransmission in favor of inhibition. This shift was due in part to increased synthesis of GABA and increased removal of glutamate from the synaptic cleft by astrocytes. The data reveal that treatment with a selective ERβ agonist results in changes opposite to those reported in estradiol-17β-treated mice and suggests that ERα and ERβ play opposing roles in the brain.neurotransmitter | glutamate toxicity | cerebral cortex | hippocampus O f the two estrogen receptors (ERs), ERα appears to be the major player in regulating the reproductive system, whereas both receptors ERα and ERβ are involved in regulation of mood and affective disorders (1, 2). Several studies show that ERα activation is anxiogenic (3-5), whereas ERβ activation is anxiolytic and controls expression of fear and anxiety-like behaviors (6-9). Not surprisingly, estradiol (E2), which binds equally well to ERα and ERβ, has unpredictable effects on abnormal psychiatric behaviors, depending on dose, treatment regimens, or animal models (10-13). In hippocampal cultures both exogenous (E2) treatment and locally synthesized E2 up-regulate ERα and down-regulate ERβ expression (14). Thus, E2 has unpredictable effects on the balance between anxiogenic and anxiolytic effects, in part because E2 has opposite effects on ERα and ERβ (15). Using subtype-selective ligands, we can begin to study the outcome of selective activation or inhibition of a particular receptor subtype involved in different behaviors.Spines and the synapses located on neurons are the sites at which neuronal communication occurs and are essential for complex behavioral phenomena and cognition. In the mature CNS, alterations in synapse structure and function continue to be a dynamic process that is of fundamental importance to learning and memory as well as other adaptive abilities of the brain. Studies...

show abstract

“…Data represent means Ϯ SEM. Scale bars, 100 m. berti et al, 2000Wang et al, 2002;Steffensen et al, 2004;Andersson et al, 2005;Kim et al, 2008). Moreover, even though the affinity of TO901317 for LXR␣ and LXR␤ may not be different, the biological effects of TO901317 often indicate a greater action through LXR␣ (Fiévet and Staels, 2009), whereas, at least in hepatocytes and astrocytes, the abundance of LXR␤ is even greater than that of LXR␣ (Tobin et al, 2000;Abildayeva et al, 2006).…”

Section: Apoe-dependent Microglial Phagocytosis Of Fibrillar A␤ Contrmentioning

confidence: 99%

Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis

Terwel¹,

Steffensen²,

Verghese³

et al. 2011

J. Neurosci.

165

115

View full text Add to dashboard Cite

Liver X receptors (LXRs) regulate immune cell function and cholesterol metabolism, both factors that are critically involved in Alzheimer's disease (AD). To investigate the therapeutic potential of long-term LXR activation in amyloid-␤ (A␤) peptide deposition in an AD model, 13-month-old, amyloid plaque-bearing APP23 mice were treated with the LXR agonist TO901317. Postmortem analysis demonstrated that TO901317 efficiently crossed the blood-brain barrier. Insoluble and soluble A␤ levels in the treated APP23 mice were reduced by 80% and 40%, respectively, compared with untreated animals. Amyloid precursor protein (APP) processing, however, was hardly changed by the compound, suggesting that the observed effects were instead mediated by A␤ disposal. Despite the profound effect on A␤ levels, spatial learning in the Morris water maze was only slightly improved by the treatment. ABCA1 (ATP-binding cassette transporter 1) and apolipoprotein E (ApoE) protein levels were increased and found to be primarily localized in astrocytes. Experiments using primary microglia demonstrated that medium derived from primary astrocytes exposed to TO901317 stimulated phagocytosis of fibrillar A␤. Conditioned medium from TO901317-treated ApoE Ϫ/Ϫ or LXR␣ Ϫ/Ϫ astrocytes did not increase phagocytosis of A␤. In APP23 mice, long-term treatment with TO901317 strongly increased the association of microglia and A␤ plaques. Short-term treatment of APP/PS1 mice with TO901317 also increased this association, which was dependent on the presence of LXR␣ and was accompanied by increased ApoE lipidation. Together, these data suggest that astrocytic LXR␣ activation and subsequent release of ApoE by astrocytes is critical for the ability of microglia to remove fibrillar A␤ in response to treatment with TO901317.

show abstract

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

Cited by 125 publications

References 54 publications

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

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

Reduction of dendritic spines and elevation of GABAergic signaling in the brains of mice treated with an estrogen receptor β ligand

Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis

Contact Info

Product

Resources

About