TY  - JOUR
AU  - Yamanaka, Mitsugu
AU  - Ishikawa, Taizo
AU  - Griep, Angelika
AU  - Axt, Daisy
AU  - Kummer, Markus P
AU  - Heneka, Michael T
TI  - PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice.
JO  - The journal of neuroscience
VL  - 32
IS  - 48
SN  - 0270-6474
CY  - Washington, DC
PB  - Soc.57413
M1  - DZNE-2020-03032
SP  - 17321-17331
PY  - 2012
AB  - 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.
KW  - Alzheimer Disease: drug therapy
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: psychology
KW  - Amyloid beta-Protein Precursor: genetics
KW  - Amyloid beta-Protein Precursor: metabolism
KW  - Animals
KW  - Behavior, Animal: drug effects
KW  - Behavior, Animal: physiology
KW  - Brain: drug effects
KW  - Brain: metabolism
KW  - Cognition: drug effects
KW  - Cognition: physiology
KW  - Disease Models, Animal
KW  - Hypoglycemic Agents: pharmacology
KW  - Hypoglycemic Agents: therapeutic use
KW  - Maze Learning: drug effects
KW  - Maze Learning: physiology
KW  - Mice
KW  - Microglia: drug effects
KW  - Microglia: metabolism
KW  - PPAR gamma: agonists
KW  - Phagocytosis: drug effects
KW  - Phagocytosis: physiology
KW  - Pioglitazone
KW  - Presenilin-1: genetics
KW  - Presenilin-1: metabolism
KW  - Thiazolidinediones: pharmacology
KW  - Thiazolidinediones: therapeutic use
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
KW  - Hypoglycemic Agents (NLM Chemicals)
KW  - PPAR gamma (NLM Chemicals)
KW  - Presenilin-1 (NLM Chemicals)
KW  - Thiazolidinediones (NLM Chemicals)
KW  - Pioglitazone (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:23197723
C2  - pmc:PMC6621845
DO  - DOI:10.1523/JNEUROSCI.1569-12.2012
UR  - https://pub.dzne.de/record/136710
ER  -