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Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor γ Agonist Treatment Reduces Amyloid β Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice.
J Biol Chem. 2015 Aug 28; 290(35):21591-602.JB

Abstract

Alzheimer disease (AD) is characterized by the extracellular accumulation of amyloid β (Aβ), which is accompanied by a robust inflammatory response in the brain. Both of these pathogenic processes are regulated by nuclear receptors, including the liver X receptors (LXRs) and peroxisome-proliferator receptor γ (PPARγ). Agonists of LXRs have been demonstrated previously to reduce Aβ levels and improve cognitive deficits in AD mouse models by inducing the transcription and lipidation of apolipoprotein E (apoE). Agonists targeting PPARγ reduce the microglial expression of proinflammatory genes and have also been shown to modulate apoE expression. Here we investigate whether a combination therapy with both LXR and PPARγ agonists results in increased benefits in an AD mouse model. We found that the LXR agonist GW3965 and the PPARγ agonist pioglitazone were individually able to increase the levels of apoE and related genes, decrease the expression of proinflammatory genes, and facilitate Aβ decreases in the hippocampus. Combined treatment with both agonists provoked a further increase in the expression of apoE and a decrease in the soluble and deposited forms of Aβ. The decrease in plaques was associated with increased colocalization between microglia and plaques. In addition, the PPARγ agonist in the combined treatment paradigm was able to counteract the elevation in plasma triglycerides that is a side effect of LXR agonist treatment. These results suggest that combined LXR/PPARγ agonist treatment merits further investigation for the treatment of AD.

Authors+Show Affiliations

From the Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106 and.the School of Medicine, University of Campinas, Campinas, Sao Paulo 13083-887, Brazil.From the Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106 and.From the Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106 and.From the Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106 and gel2@case.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26163517

Citation

Skerrett, Rebecca, et al. "Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor Γ Agonist Treatment Reduces Amyloid Β Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice." The Journal of Biological Chemistry, vol. 290, no. 35, 2015, pp. 21591-602.
Skerrett R, Pellegrino MP, Casali BT, et al. Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor γ Agonist Treatment Reduces Amyloid β Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice. J Biol Chem. 2015;290(35):21591-602.
Skerrett, R., Pellegrino, M. P., Casali, B. T., Taraboanta, L., & Landreth, G. E. (2015). Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor γ Agonist Treatment Reduces Amyloid β Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice. The Journal of Biological Chemistry, 290(35), 21591-602. https://doi.org/10.1074/jbc.M115.652008
Skerrett R, et al. Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor Γ Agonist Treatment Reduces Amyloid Β Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice. J Biol Chem. 2015 Aug 28;290(35):21591-602. PubMed PMID: 26163517.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor γ Agonist Treatment Reduces Amyloid β Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice. AU - Skerrett,Rebecca, AU - Pellegrino,Mateus P, AU - Casali,Brad T, AU - Taraboanta,Laura, AU - Landreth,Gary E, Y1 - 2015/07/10/ PY - 2015/03/13/received PY - 2015/7/12/entrez PY - 2015/7/15/pubmed PY - 2015/12/15/medline KW - Alzheimer disease KW - amyloid β (Aβ) KW - apolipoprotein E (apoE) KW - liver X receptor (LXR) KW - microglia KW - peroxisome proliferator-activated receptor (PPAR) SP - 21591 EP - 602 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 290 IS - 35 N2 - Alzheimer disease (AD) is characterized by the extracellular accumulation of amyloid β (Aβ), which is accompanied by a robust inflammatory response in the brain. Both of these pathogenic processes are regulated by nuclear receptors, including the liver X receptors (LXRs) and peroxisome-proliferator receptor γ (PPARγ). Agonists of LXRs have been demonstrated previously to reduce Aβ levels and improve cognitive deficits in AD mouse models by inducing the transcription and lipidation of apolipoprotein E (apoE). Agonists targeting PPARγ reduce the microglial expression of proinflammatory genes and have also been shown to modulate apoE expression. Here we investigate whether a combination therapy with both LXR and PPARγ agonists results in increased benefits in an AD mouse model. We found that the LXR agonist GW3965 and the PPARγ agonist pioglitazone were individually able to increase the levels of apoE and related genes, decrease the expression of proinflammatory genes, and facilitate Aβ decreases in the hippocampus. Combined treatment with both agonists provoked a further increase in the expression of apoE and a decrease in the soluble and deposited forms of Aβ. The decrease in plaques was associated with increased colocalization between microglia and plaques. In addition, the PPARγ agonist in the combined treatment paradigm was able to counteract the elevation in plasma triglycerides that is a side effect of LXR agonist treatment. These results suggest that combined LXR/PPARγ agonist treatment merits further investigation for the treatment of AD. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/26163517/Combined_Liver_X_Receptor/Peroxisome_Proliferator_activated_Receptor_γ_Agonist_Treatment_Reduces_Amyloid_β_Levels_and_Improves_Behavior_in_Amyloid_Precursor_Protein/Presenilin_1_Mice_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=26163517 DB - PRIME DP - Unbound Medicine ER -