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Expression profiling in APP23 mouse brain: inhibition of Abeta amyloidosis and inflammation in response to LXR agonist treatment.

Lefterov I, Bookout A, Wang Z, Staufenbiel M, Mangelsdorf D, Koldamova R - Mol Neurodegener (2007)

Bottom Line: Additional treatment experiments demonstrated an increase of soluble apolipoproteins E and A-I and a decrease of insoluble Abeta.The results show that LXR agonists could alleviate AD pathology by acting on amyloid deposition and brain inflammation.An increased understanding of the LXR controlled regulation of Abeta aggregation and clearance systems will lead to the development of more specific and powerful agonists targeting LXR for the treatment of AD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15219, USA. iliyal@pitt.edu.

ABSTRACT

Background: Recent studies demonstrate that in addition to its modulatory effect on APP processing, in vivo application of Liver X Receptor agonist T0901317 (T0) to APP transgenic and non-transgenic mice decreases the level of Abeta42. Moreover, in young Tg2576 mice T0 completely reversed contextual memory deficits. Compared to other tissues, the regulatory functions of LXRs in brain remain largely unexplored and our knowledge so far is limited to the cholesterol transporters and apoE. In this study we applied T0 to APP23 mice for various times and examined gene and protein expression. We also performed a series of experiments with primary brain cells derived from wild type and LXR knockout mice subjected to various LXR agonist treatments and inflammatory stimuli.

Results: We demonstrate an upregulation of genes related to lipid metabolism/transport, metabolism of xenobiotics and detoxification. Downregulated genes are involved in immune response and inflammation, cell death and apoptosis. Additional treatment experiments demonstrated an increase of soluble apolipoproteins E and A-I and a decrease of insoluble Abeta. In primary LXRwt but not in LXRalpha-/-beta-/- microglia and astrocytes LXR agonists suppressed the inflammatory response induced by LPS or fibrillar Abeta.

Conclusion: The results show that LXR agonists could alleviate AD pathology by acting on amyloid deposition and brain inflammation. An increased understanding of the LXR controlled regulation of Abeta aggregation and clearance systems will lead to the development of more specific and powerful agonists targeting LXR for the treatment of AD.

No MeSH data available.


Related in: MedlinePlus

T0 down-regulates LPS- and Aβ – induced iNOS synthesis and NO production in primary rat microglia. Rat microglia was pre-treated with increasing concentration of T0 (LPS+T0) or vehicle (LPS only) prior to the addition of LPS (100 ng/ml) and the ligand was co-applied with LPS. Control cells received vehicle only (veh). Cells were harvested 24 hours after LPS administration and the expression of iNOS was examined by WB. A and B: Concentration dependent effect of T0 on LPS-induced iNOS protein and NO production in primary rat microglia. Microglia was pre-treated with increasing concentration of T0 (LPS+T0) or vehicle (LPS only) prior to the addition of LPS (100 ng/ml) and the ligand was co-applied with LPS. Control cells received vehicle only (veh). Cells were harvested 24 after LPS treatment and the expression of iNOS was examined by WB (A). NO in the conditioned media was measured by Griess reagent (B). C and D: T0 (10 μM) inhibits NO production (C) and iNOS protein (D) induced by fibrillar Aβ25–35 or Aβ42 peptides applied for 24 hours to microglia. Note that T0 decreases iNOS even bellow its basal level if applied with Aβ (in D, veh versus Aβ25–35+T0, p < 0.01). Values are means ± SEM; two-tailed Student's t test; *, p < 0.05.
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Figure 5: T0 down-regulates LPS- and Aβ – induced iNOS synthesis and NO production in primary rat microglia. Rat microglia was pre-treated with increasing concentration of T0 (LPS+T0) or vehicle (LPS only) prior to the addition of LPS (100 ng/ml) and the ligand was co-applied with LPS. Control cells received vehicle only (veh). Cells were harvested 24 hours after LPS administration and the expression of iNOS was examined by WB. A and B: Concentration dependent effect of T0 on LPS-induced iNOS protein and NO production in primary rat microglia. Microglia was pre-treated with increasing concentration of T0 (LPS+T0) or vehicle (LPS only) prior to the addition of LPS (100 ng/ml) and the ligand was co-applied with LPS. Control cells received vehicle only (veh). Cells were harvested 24 after LPS treatment and the expression of iNOS was examined by WB (A). NO in the conditioned media was measured by Griess reagent (B). C and D: T0 (10 μM) inhibits NO production (C) and iNOS protein (D) induced by fibrillar Aβ25–35 or Aβ42 peptides applied for 24 hours to microglia. Note that T0 decreases iNOS even bellow its basal level if applied with Aβ (in D, veh versus Aβ25–35+T0, p < 0.01). Values are means ± SEM; two-tailed Student's t test; *, p < 0.05.

Mentions: Next, we examined if LXR ligands decrease the secretion of proinflammatory cytokines in primary rat microglial cells treated with LPS or fibrillar Aβ25–35 and Aβ42 peptides. First, we examined the effect of T0 on nitric oxide (NO) production and iNOS protein level which are normally increased in response to LPS. As shown on Fig. 5A and 5B, T0 applied 18 hr prior to and then co-applied with LPS down-regulated the expression of iNOS and NO production in rat microglia in a concentration-dependent manner. Similarly, T0 (used at 10 μM concentration) inhibited the expression of iNOS in Aβ treated cells and production of NO in the conditioned media (Fig. 5C and 5D). Noticeably, T0 decreases iNOS protein even bellow its basal level (p < 0.01, vehicle versus Aβ25–35+T0 in Fig. 5D).


Expression profiling in APP23 mouse brain: inhibition of Abeta amyloidosis and inflammation in response to LXR agonist treatment.

Lefterov I, Bookout A, Wang Z, Staufenbiel M, Mangelsdorf D, Koldamova R - Mol Neurodegener (2007)

T0 down-regulates LPS- and Aβ – induced iNOS synthesis and NO production in primary rat microglia. Rat microglia was pre-treated with increasing concentration of T0 (LPS+T0) or vehicle (LPS only) prior to the addition of LPS (100 ng/ml) and the ligand was co-applied with LPS. Control cells received vehicle only (veh). Cells were harvested 24 hours after LPS administration and the expression of iNOS was examined by WB. A and B: Concentration dependent effect of T0 on LPS-induced iNOS protein and NO production in primary rat microglia. Microglia was pre-treated with increasing concentration of T0 (LPS+T0) or vehicle (LPS only) prior to the addition of LPS (100 ng/ml) and the ligand was co-applied with LPS. Control cells received vehicle only (veh). Cells were harvested 24 after LPS treatment and the expression of iNOS was examined by WB (A). NO in the conditioned media was measured by Griess reagent (B). C and D: T0 (10 μM) inhibits NO production (C) and iNOS protein (D) induced by fibrillar Aβ25–35 or Aβ42 peptides applied for 24 hours to microglia. Note that T0 decreases iNOS even bellow its basal level if applied with Aβ (in D, veh versus Aβ25–35+T0, p < 0.01). Values are means ± SEM; two-tailed Student's t test; *, p < 0.05.
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Figure 5: T0 down-regulates LPS- and Aβ – induced iNOS synthesis and NO production in primary rat microglia. Rat microglia was pre-treated with increasing concentration of T0 (LPS+T0) or vehicle (LPS only) prior to the addition of LPS (100 ng/ml) and the ligand was co-applied with LPS. Control cells received vehicle only (veh). Cells were harvested 24 hours after LPS administration and the expression of iNOS was examined by WB. A and B: Concentration dependent effect of T0 on LPS-induced iNOS protein and NO production in primary rat microglia. Microglia was pre-treated with increasing concentration of T0 (LPS+T0) or vehicle (LPS only) prior to the addition of LPS (100 ng/ml) and the ligand was co-applied with LPS. Control cells received vehicle only (veh). Cells were harvested 24 after LPS treatment and the expression of iNOS was examined by WB (A). NO in the conditioned media was measured by Griess reagent (B). C and D: T0 (10 μM) inhibits NO production (C) and iNOS protein (D) induced by fibrillar Aβ25–35 or Aβ42 peptides applied for 24 hours to microglia. Note that T0 decreases iNOS even bellow its basal level if applied with Aβ (in D, veh versus Aβ25–35+T0, p < 0.01). Values are means ± SEM; two-tailed Student's t test; *, p < 0.05.
Mentions: Next, we examined if LXR ligands decrease the secretion of proinflammatory cytokines in primary rat microglial cells treated with LPS or fibrillar Aβ25–35 and Aβ42 peptides. First, we examined the effect of T0 on nitric oxide (NO) production and iNOS protein level which are normally increased in response to LPS. As shown on Fig. 5A and 5B, T0 applied 18 hr prior to and then co-applied with LPS down-regulated the expression of iNOS and NO production in rat microglia in a concentration-dependent manner. Similarly, T0 (used at 10 μM concentration) inhibited the expression of iNOS in Aβ treated cells and production of NO in the conditioned media (Fig. 5C and 5D). Noticeably, T0 decreases iNOS protein even bellow its basal level (p < 0.01, vehicle versus Aβ25–35+T0 in Fig. 5D).

Bottom Line: Additional treatment experiments demonstrated an increase of soluble apolipoproteins E and A-I and a decrease of insoluble Abeta.The results show that LXR agonists could alleviate AD pathology by acting on amyloid deposition and brain inflammation.An increased understanding of the LXR controlled regulation of Abeta aggregation and clearance systems will lead to the development of more specific and powerful agonists targeting LXR for the treatment of AD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15219, USA. iliyal@pitt.edu.

ABSTRACT

Background: Recent studies demonstrate that in addition to its modulatory effect on APP processing, in vivo application of Liver X Receptor agonist T0901317 (T0) to APP transgenic and non-transgenic mice decreases the level of Abeta42. Moreover, in young Tg2576 mice T0 completely reversed contextual memory deficits. Compared to other tissues, the regulatory functions of LXRs in brain remain largely unexplored and our knowledge so far is limited to the cholesterol transporters and apoE. In this study we applied T0 to APP23 mice for various times and examined gene and protein expression. We also performed a series of experiments with primary brain cells derived from wild type and LXR knockout mice subjected to various LXR agonist treatments and inflammatory stimuli.

Results: We demonstrate an upregulation of genes related to lipid metabolism/transport, metabolism of xenobiotics and detoxification. Downregulated genes are involved in immune response and inflammation, cell death and apoptosis. Additional treatment experiments demonstrated an increase of soluble apolipoproteins E and A-I and a decrease of insoluble Abeta. In primary LXRwt but not in LXRalpha-/-beta-/- microglia and astrocytes LXR agonists suppressed the inflammatory response induced by LPS or fibrillar Abeta.

Conclusion: The results show that LXR agonists could alleviate AD pathology by acting on amyloid deposition and brain inflammation. An increased understanding of the LXR controlled regulation of Abeta aggregation and clearance systems will lead to the development of more specific and powerful agonists targeting LXR for the treatment of AD.

No MeSH data available.


Related in: MedlinePlus