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
Hauptverfasser: Mandrekar-Colucci, Shweta, Karlo, J Colleen, Landreth, Gary E
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creator Mandrekar-Colucci, Shweta
Karlo, J Colleen
Landreth, Gary E
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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source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central
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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