Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease
Alzheimer's disease is associated with a disruption of amyloid β (Aβ) homeostasis, resulting in the accumulation and subsequent deposition of Aβ peptides within the brain. The peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated nuclear receptor that acts in a coupled meta...
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Veröffentlicht in: | The Journal of neuroscience 2012-07, Vol.32 (30), p.10117-10128 |
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description | Alzheimer's disease is associated with a disruption of amyloid β (Aβ) homeostasis, resulting in the accumulation and subsequent deposition of Aβ peptides within the brain. The peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated nuclear receptor that acts in a coupled metabolic cycle with Liver X Receptors (LXRs) to increase brain apolipoprotein E (apoE) levels. apoE functions to promote the proteolytic clearance of soluble forms of Aβ, and we found that the synthetic PPARγ agonist, pioglitazone, stimulated Aβ degradation by both microglia and astrocytes in an LXR and apoE-dependent manner. Remarkably, a brief 9 d oral treatment of APPswe/PS1Δe9 mice with pioglitazone resulted in dramatic reductions in brain levels of soluble and insoluble Aβ levels which correlated with the loss of both diffuse and dense-core plaques within the cortex. The removal of preexisting amyloid deposits was associated with the appearance of abundant Aβ-laden microglia and astrocytes. Pioglitazone treatment resulted in the phenotypic polarization of microglial cells from a proinflammatory M1 state, into an anti-inflammatory M2 state that was associated with enhanced phagocytosis of deposited forms of amyloid. The reduction in amyloid levels was associated with a reversal of contextual memory deficits in the drug-treated mice. These data provide a mechanistic explanation for how PPARγ activation facilitates amyloid clearance and supports the therapeutic utility of PPARγ agonists for the treatment of Alzheimer's disease. |
doi_str_mv | 10.1523/JNEUROSCI.5268-11.2012 |
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The peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated nuclear receptor that acts in a coupled metabolic cycle with Liver X Receptors (LXRs) to increase brain apolipoprotein E (apoE) levels. apoE functions to promote the proteolytic clearance of soluble forms of Aβ, and we found that the synthetic PPARγ agonist, pioglitazone, stimulated Aβ degradation by both microglia and astrocytes in an LXR and apoE-dependent manner. Remarkably, a brief 9 d oral treatment of APPswe/PS1Δe9 mice with pioglitazone resulted in dramatic reductions in brain levels of soluble and insoluble Aβ levels which correlated with the loss of both diffuse and dense-core plaques within the cortex. The removal of preexisting amyloid deposits was associated with the appearance of abundant Aβ-laden microglia and astrocytes. Pioglitazone treatment resulted in the phenotypic polarization of microglial cells from a proinflammatory M1 state, into an anti-inflammatory M2 state that was associated with enhanced phagocytosis of deposited forms of amyloid. The reduction in amyloid levels was associated with a reversal of contextual memory deficits in the drug-treated mice. 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The peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated nuclear receptor that acts in a coupled metabolic cycle with Liver X Receptors (LXRs) to increase brain apolipoprotein E (apoE) levels. apoE functions to promote the proteolytic clearance of soluble forms of Aβ, and we found that the synthetic PPARγ agonist, pioglitazone, stimulated Aβ degradation by both microglia and astrocytes in an LXR and apoE-dependent manner. Remarkably, a brief 9 d oral treatment of APPswe/PS1Δe9 mice with pioglitazone resulted in dramatic reductions in brain levels of soluble and insoluble Aβ levels which correlated with the loss of both diffuse and dense-core plaques within the cortex. The removal of preexisting amyloid deposits was associated with the appearance of abundant Aβ-laden microglia and astrocytes. Pioglitazone treatment resulted in the phenotypic polarization of microglial cells from a proinflammatory M1 state, into an anti-inflammatory M2 state that was associated with enhanced phagocytosis of deposited forms of amyloid. The reduction in amyloid levels was associated with a reversal of contextual memory deficits in the drug-treated mice. 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Karlo, J Colleen ; Landreth, Gary E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c352t-476cd6917137195d90568a0305d08e09541fb93b8d409dbdbbe51ff95787337b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Alzheimer Disease - drug therapy</topic><topic>Alzheimer Disease - metabolism</topic><topic>Amyloid beta-Peptides - pharmacology</topic><topic>Animals</topic><topic>Apolipoproteins E - metabolism</topic><topic>Astrocytes - cytology</topic><topic>Astrocytes - drug effects</topic><topic>Astrocytes - metabolism</topic><topic>Brain - drug effects</topic><topic>Brain - metabolism</topic><topic>Cells, Cultured</topic><topic>Cognition - drug effects</topic><topic>Cognition - physiology</topic><topic>Disease Models, Animal</topic><topic>Liver X Receptors</topic><topic>Maze Learning - drug effects</topic><topic>Maze Learning - physiology</topic><topic>Mice</topic><topic>Microglia - cytology</topic><topic>Microglia - drug effects</topic><topic>Microglia - metabolism</topic><topic>Orphan Nuclear Receptors - metabolism</topic><topic>Peptide Fragments - pharmacology</topic><topic>PPAR gamma - agonists</topic><topic>PPAR gamma - metabolism</topic><topic>Signal Transduction - physiology</topic><topic>Thiazolidinediones - pharmacology</topic><topic>Thiazolidinediones - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mandrekar-Colucci, Shweta</creatorcontrib><creatorcontrib>Karlo, J Colleen</creatorcontrib><creatorcontrib>Landreth, Gary E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>Animal Behavior Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mandrekar-Colucci, Shweta</au><au>Karlo, J Colleen</au><au>Landreth, Gary E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease</atitle><jtitle>The Journal of neuroscience</jtitle><addtitle>J Neurosci</addtitle><date>2012-07-25</date><risdate>2012</risdate><volume>32</volume><issue>30</issue><spage>10117</spage><epage>10128</epage><pages>10117-10128</pages><issn>1529-2401</issn><issn>0270-6474</issn><eissn>1529-2401</eissn><abstract>Alzheimer's disease is associated with a disruption of amyloid β (Aβ) homeostasis, resulting in the accumulation and subsequent deposition of Aβ peptides within the brain. The peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated nuclear receptor that acts in a coupled metabolic cycle with Liver X Receptors (LXRs) to increase brain apolipoprotein E (apoE) levels. apoE functions to promote the proteolytic clearance of soluble forms of Aβ, and we found that the synthetic PPARγ agonist, pioglitazone, stimulated Aβ degradation by both microglia and astrocytes in an LXR and apoE-dependent manner. Remarkably, a brief 9 d oral treatment of APPswe/PS1Δe9 mice with pioglitazone resulted in dramatic reductions in brain levels of soluble and insoluble Aβ levels which correlated with the loss of both diffuse and dense-core plaques within the cortex. The removal of preexisting amyloid deposits was associated with the appearance of abundant Aβ-laden microglia and astrocytes. 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subjects | Alzheimer Disease - drug therapy Alzheimer Disease - metabolism Amyloid beta-Peptides - pharmacology Animals Apolipoproteins E - metabolism Astrocytes - cytology Astrocytes - drug effects Astrocytes - metabolism Brain - drug effects Brain - metabolism Cells, Cultured Cognition - drug effects Cognition - physiology Disease Models, Animal Liver X Receptors Maze Learning - drug effects Maze Learning - physiology Mice Microglia - cytology Microglia - drug effects Microglia - metabolism Orphan Nuclear Receptors - metabolism Peptide Fragments - pharmacology PPAR gamma - agonists PPAR gamma - metabolism Signal Transduction - physiology Thiazolidinediones - pharmacology Thiazolidinediones - therapeutic use |
title | Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease |
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