Journal Article

DZNE-2020-03032

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice.

Yamanaka, M. ; Ishikawa, T. ; Griep, A. ; Axt, D. ; Kummer, M. P. ; Heneka, M. T. (Last author)DZNE*

2012
Soc.57413 Washington, DC

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Please use a persistent id in citations: doi:10.1523/JNEUROSCI.1569-12.2012

Abstract: Alzheimer's disease (AD) is characterized by the extracellular deposition of amyloid-β (Aβ), neurofibrillary tangle formation, and a microglial-driven inflammatory response. Chronic inflammatory activation compromises microglial clearance functions. Because peroxisome proliferator-activated receptor γ (PPARγ) agonists suppress inflammatory gene expression, we tested whether activation of PPARγ would also result in improved microglial Aβ phagocytosis. The PPARγ agonist pioglitazone and a novel selective PPARα/γ modulator, DSP-8658, currently in clinical development for the treatment of type 2 diabetes, enhanced the microglial uptake of Aβ in a PPARγ-dependent manner. This PPARγ-stimulated increase of Aβ phagocytosis was mediated by the upregulation of scavenger receptor CD36 expression. In addition, combined treatment with agonists for the heterodimeric binding partners of PPARγ, the retinoid X receptors (RXRs), showed additive enhancement of the Aβ uptake that was mediated by RXRα activation. Evaluation of DSP-8658 in the amyloid precursor protein/presenilin 1 mouse model confirmed an increased microglial Aβ phagocytosis in vivo, which subsequently resulted in a reduction of cortical and hippocampal Aβ levels. Furthermore, DSP-8658-treated mice showed improved spatial memory performance. Therefore, stimulation of microglial clearance by simultaneous activation of the PPARγ/RXRα heterodimer may prove beneficial in prevention of AD.

Keyword(s): Alzheimer Disease: drug therapy (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: psychology (MeSH) ; Amyloid beta-Protein Precursor: genetics (MeSH) ; Amyloid beta-Protein Precursor: metabolism (MeSH) ; Animals (MeSH) ; Behavior, Animal: drug effects (MeSH) ; Behavior, Animal: physiology (MeSH) ; Brain: drug effects (MeSH) ; Brain: metabolism (MeSH) ; Cognition: drug effects (MeSH) ; Cognition: physiology (MeSH) ; Disease Models, Animal (MeSH) ; Hypoglycemic Agents: pharmacology (MeSH) ; Hypoglycemic Agents: therapeutic use (MeSH) ; Maze Learning: drug effects (MeSH) ; Maze Learning: physiology (MeSH) ; Mice (MeSH) ; Microglia: drug effects (MeSH) ; Microglia: metabolism (MeSH) ; PPAR gamma: agonists (MeSH) ; Phagocytosis: drug effects (MeSH) ; Phagocytosis: physiology (MeSH) ; Pioglitazone (MeSH) ; Presenilin-1: genetics (MeSH) ; Presenilin-1: metabolism (MeSH) ; Thiazolidinediones: pharmacology (MeSH) ; Thiazolidinediones: therapeutic use (MeSH) ; Amyloid beta-Protein Precursor ; Hypoglycemic Agents ; PPAR gamma ; Presenilin-1 ; Thiazolidinediones ; Pioglitazone

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Contributing Institute(s):

1. DZNE before 2020 (Pre 2020)
2. Neuroinflammation, Biomarker (AG Heneka2)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2012

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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