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P2‐279: PPAR gamma/RXR induced and CD36‐mediated Abeta phagocytosis results in cognitive improvement in APP/PS1 mice
Author(s) -
Yamanaka Mitsugu,
Kurzwelly Delia,
Reyes Elisabet,
Heneka Michael
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.1158
Subject(s) - microglia , cd36 , retinoid x receptor , peroxisome proliferator activated receptor , scavenger receptor , receptor , endocrinology , chemistry , medicine , biology , nuclear receptor , biochemistry , inflammation , lipoprotein , cholesterol , transcription factor , gene
Background: Alzheimer’s disease (AD) is characterized by chronic deposition of amyloid-beta (Abeta) and by a microglial-driven inflammatory response. Recent evidence indicates that peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists ameliorate not only glucose metabolism but alsomild cognitive impairment in humans. DSP-8658 is a novel selective PPAR alpha/gamma modulator currently under clinical development for the treatment of type 2 diabetes. In this study, we investigated the therapeutic potential of DSP-8658 for AD. Methods: Rat primary microglia cells were prepared from mixed neuronal cultures prepared from newborn rats. Microglia phagocytosis of FAM-labelled fibrillar Abeta1-42 was measured using a plate reader. siRNA experiments were performed using Nucleofector II and the mouse macrophage nucleofection kit. CD36 and PPAR gamma expression were assayed byWestern-blot and RT-PCR. Three months old of APP/PS1 transgenic mice were treated with DSP-8658 containing diet for 3 months. Cognitive function was evaluated byMorrisWater Maze. Abeta levels in the brain were assayed by ELISA. Microglial phagocytosis was quantified in vivo by methoxy-04.Results:DSP-8658 enhanced the uptake of Abeta in rodent primarymicroglia. Of note, this effect was mediated by PPAR gamma positively regulating the expression of scavenger receptor CD36. A combination of DSP-8658 with several RXR agonists, including bexarotene and retinoic acid showed additive enhancement of microglial Abeta uptake. Western blot and siRNA experiments found that RXR alpha is more abundant and functionally important than RXR beta in primary microglia. Moreover, in order to evaluate the effect of DSP8658 on mouse model of AD, APP/PS1 transgenic mice were treated with DSP-8658. DSP-8658 treatment increased microglial Abeta phagocytosis in vivo resulting in an overall reduction of Abeta40 and Abeta42 levels in cortex and hippocampus and improved spatial memory performance. Conclusions: Together these data suggest that activation of PPAR gamma by DSP-8658 alone or more effectively in concert with RXR enhances microglial Abeta phagocytosis via upregulation of CD36. Based on the verification of the above results in vivo, DSP-8658 may serve as an attractive therapeutic agent for AD treatment.