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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

Verification of array data. A, B and C. 6-month old APP23 animals were treated with T0 for 25 days at a dose of 50 mg/kg/day (n = 5); control mice (n = 5) received vehicle and gene expression profiles were generated using Affymetrix 430A 2.0 mouse gene chips. RT-QPCR for selected up-regulated (A and B) and down-regulated (C) genes from T0-treated and control mice was performed on the same total RNA as used for the array assays and the results compared to those from the array experiments. Fold changes observed in arrays (white bars) and RT-QPCR (grey bars) for each gene tested are arranged adjacently (± S.E.M.) and were statistically significant (p < 0.05 using two-tailed Student's t test). D. 6–7 month old APP23 animals were treated for 24 hours with T0 (50 mg/kg body weight, n = 5); control mice (n = 5) received vehicle. Total RNA was extracted from homogenized cortices and hippocampi and the expression of selected LXR target genes was determined by RT-QPCR.
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Figure 1: Verification of array data. A, B and C. 6-month old APP23 animals were treated with T0 for 25 days at a dose of 50 mg/kg/day (n = 5); control mice (n = 5) received vehicle and gene expression profiles were generated using Affymetrix 430A 2.0 mouse gene chips. RT-QPCR for selected up-regulated (A and B) and down-regulated (C) genes from T0-treated and control mice was performed on the same total RNA as used for the array assays and the results compared to those from the array experiments. Fold changes observed in arrays (white bars) and RT-QPCR (grey bars) for each gene tested are arranged adjacently (± S.E.M.) and were statistically significant (p < 0.05 using two-tailed Student's t test). D. 6–7 month old APP23 animals were treated for 24 hours with T0 (50 mg/kg body weight, n = 5); control mice (n = 5) received vehicle. Total RNA was extracted from homogenized cortices and hippocampi and the expression of selected LXR target genes was determined by RT-QPCR.

Mentions: Previously we have demonstrated that short T0 treatment decreased the level of soluble Aβ in 3-month old pre-depositing APP23 mice in correlation with an increased ABCA1 level [21]. To determine the effect of activated LXRs on genes involved in the initial stages of Aβ deposition in older mice we treated 6-month old APP23 animals with T0 for 25 days (every day at a dose of 50 mg/kg body weight; control mice received vehicle; n = 5 for both groups). We specifically chose APP23 mice at an age when there is an increase in insoluble Aβ peptides, although actual amyloid plaques are still rare. At the end of the treatment total RNA was isolated from cortices and hippocampi and gene expression profiles for both groups were generated using Affymetrix 430A 2.0 mouse gene chips. The activation status of LXRs was confirmed by the increased level of ABCA1 mRNA of T0 versus vehicle treated mice as measured by RT-QPCR (Fig. 1A).


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)

Verification of array data. A, B and C. 6-month old APP23 animals were treated with T0 for 25 days at a dose of 50 mg/kg/day (n = 5); control mice (n = 5) received vehicle and gene expression profiles were generated using Affymetrix 430A 2.0 mouse gene chips. RT-QPCR for selected up-regulated (A and B) and down-regulated (C) genes from T0-treated and control mice was performed on the same total RNA as used for the array assays and the results compared to those from the array experiments. Fold changes observed in arrays (white bars) and RT-QPCR (grey bars) for each gene tested are arranged adjacently (± S.E.M.) and were statistically significant (p < 0.05 using two-tailed Student's t test). D. 6–7 month old APP23 animals were treated for 24 hours with T0 (50 mg/kg body weight, n = 5); control mice (n = 5) received vehicle. Total RNA was extracted from homogenized cortices and hippocampi and the expression of selected LXR target genes was determined by RT-QPCR.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2214725&req=5

Figure 1: Verification of array data. A, B and C. 6-month old APP23 animals were treated with T0 for 25 days at a dose of 50 mg/kg/day (n = 5); control mice (n = 5) received vehicle and gene expression profiles were generated using Affymetrix 430A 2.0 mouse gene chips. RT-QPCR for selected up-regulated (A and B) and down-regulated (C) genes from T0-treated and control mice was performed on the same total RNA as used for the array assays and the results compared to those from the array experiments. Fold changes observed in arrays (white bars) and RT-QPCR (grey bars) for each gene tested are arranged adjacently (± S.E.M.) and were statistically significant (p < 0.05 using two-tailed Student's t test). D. 6–7 month old APP23 animals were treated for 24 hours with T0 (50 mg/kg body weight, n = 5); control mice (n = 5) received vehicle. Total RNA was extracted from homogenized cortices and hippocampi and the expression of selected LXR target genes was determined by RT-QPCR.
Mentions: Previously we have demonstrated that short T0 treatment decreased the level of soluble Aβ in 3-month old pre-depositing APP23 mice in correlation with an increased ABCA1 level [21]. To determine the effect of activated LXRs on genes involved in the initial stages of Aβ deposition in older mice we treated 6-month old APP23 animals with T0 for 25 days (every day at a dose of 50 mg/kg body weight; control mice received vehicle; n = 5 for both groups). We specifically chose APP23 mice at an age when there is an increase in insoluble Aβ peptides, although actual amyloid plaques are still rare. At the end of the treatment total RNA was isolated from cortices and hippocampi and gene expression profiles for both groups were generated using Affymetrix 430A 2.0 mouse gene chips. The activation status of LXRs was confirmed by the increased level of ABCA1 mRNA of T0 versus vehicle treated mice as measured by RT-QPCR (Fig. 1A).

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