PMID- 23197723
OWN - NLM
STAT- MEDLINE
DCOM- 20130219
LR  - 20220408
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 32
IP  - 48
DP  - 2012 Nov 28
TI  - PPARgamma/RXRalpha-induced and CD36-mediated microglial amyloid-beta phagocytosis results in 
      cognitive improvement in amyloid precursor protein/presenilin 1 mice.
PG  - 17321-31
LID - 10.1523/JNEUROSCI.1569-12.2012 [doi]
AB  - Alzheimer's disease (AD) is characterized by the extracellular deposition of 
      amyloid-beta (Abeta), neurofibrillary tangle formation, and a microglial-driven 
      inflammatory response. Chronic inflammatory activation compromises microglial 
      clearance functions. Because peroxisome proliferator-activated receptor gamma (PPARgamma) 
      agonists suppress inflammatory gene expression, we tested whether activation of 
      PPARgamma would also result in improved microglial Abeta phagocytosis. The PPARgamma agonist 
      pioglitazone and a novel selective PPARalpha/gamma modulator, DSP-8658, currently in 
      clinical development for the treatment of type 2 diabetes, enhanced the 
      microglial uptake of Abeta in a PPARgamma-dependent manner. This PPARgamma-stimulated 
      increase of Abeta phagocytosis was mediated by the upregulation of scavenger 
      receptor CD36 expression. In addition, combined treatment with agonists for the 
      heterodimeric binding partners of PPARgamma, the retinoid X receptors (RXRs), showed 
      additive enhancement of the Abeta uptake that was mediated by RXRalpha activation. 
      Evaluation of DSP-8658 in the amyloid precursor protein/presenilin 1 mouse model 
      confirmed an increased microglial Abeta phagocytosis in vivo, which subsequently 
      resulted in a reduction of cortical and hippocampal Abeta levels. Furthermore, 
      DSP-8658-treated mice showed improved spatial memory performance. Therefore, 
      stimulation of microglial clearance by simultaneous activation of the PPARgamma/RXRalpha 
      heterodimer may prove beneficial in prevention of AD.
FAU - Yamanaka, Mitsugu
AU  - Yamanaka M
AD  - Clinical Neuroscience Unit, Department of Neurology, University of Bonn Medical 
      Center, 53127 Bonn, Germany.
FAU - Ishikawa, Taizo
AU  - Ishikawa T
FAU - Griep, Angelika
AU  - Griep A
FAU - Axt, Daisy
AU  - Axt D
FAU - Kummer, Markus P
AU  - Kummer MP
FAU - Heneka, Michael T
AU  - Heneka MT
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (PPAR gamma)
RN  - 0 (Presenilin-1)
RN  - 0 (Thiazolidinediones)
RN  - X4OV71U42S (Pioglitazone)
SB  - IM
CIN - J Neurosci. 2013 Mar 20;33(12):5083-4. PMID: 23516274
MH  - Alzheimer Disease/*drug therapy/metabolism/psychology
MH  - Amyloid beta-Protein Precursor/genetics/metabolism
MH  - Animals
MH  - Behavior, Animal/drug effects/physiology
MH  - Brain/*drug effects/metabolism
MH  - Cognition/drug effects/physiology
MH  - Disease Models, Animal
MH  - Hypoglycemic Agents/pharmacology/therapeutic use
MH  - Maze Learning/*drug effects/physiology
MH  - Mice
MH  - Microglia/*drug effects/metabolism
MH  - PPAR gamma/*agonists
MH  - Phagocytosis/*drug effects/physiology
MH  - Pioglitazone
MH  - Presenilin-1/genetics/metabolism
MH  - Thiazolidinediones/pharmacology/therapeutic use
PMC - PMC6621845
EDAT- 2012/12/01 06:00
MHDA- 2013/02/21 06:00
PMCR- 2013/05/28
CRDT- 2012/12/01 06:00
PHST- 2012/12/01 06:00 [entrez]
PHST- 2012/12/01 06:00 [pubmed]
PHST- 2013/02/21 06:00 [medline]
PHST- 2013/05/28 00:00 [pmc-release]
AID - 32/48/17321 [pii]
AID - 3810504 [pii]
AID - 10.1523/JNEUROSCI.1569-12.2012 [doi]
PST - ppublish
SO  - J Neurosci. 2012 Nov 28;32(48):17321-31. doi: 10.1523/JNEUROSCI.1569-12.2012.