Antagonist of peroxisome proliferator-activated receptor gamma induces cerebellar amyloid-beta levels and motor dysfunction in APP/PS1 transgenic mice.
Recent evidences show that peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in the modulation of the amyloid-beta (Abeta) cascade causing Alzheimer's disease (AD) and treatment with PPARgamma agonists protects against AD pathology. However, the function of PPARgamma steady-state activity in Abeta cascade and AD pathology remains unclear. In this study, an antagonist of PPARgamma, GW9662, was injected into the fourth ventricle of APP/PS1 transgenic mice to inhibit PPARgamma activity in cerebellum. The results show that inhibition of PPARgamma significantly induced Abeta levels in cerebellum and caused cerebellar motor dysfunction in APP/PS1 transgenic mice. Moreover, GW9662 treatment markedly decreased the cerebellar levels of insulin-degrading enzyme (IDE), which is responsible for the cellular degradation of Abeta. Since cerebellum is spared from significant Abeta accumulation and neurotoxicity in AD patients and animal models, these findings suggest a crucial role of PPARgamma steady-state activity in protection of cerebellum against AD pathology.
Protein Science Key Laboratory of the Ministry of Education, Department of Biological Sciences and Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, PR China.
Jing
J
Du
Bing
B
Sun
Kui
K
Chen
Li
L
Fan
Zhao
Z
Wang
D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002531:Cerebellum / Q000378:metabolism* / Q000503:physiopathology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009069:Movement Disorders / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*
C457499:2-chloro-5-nitrobenzanilide; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000813:Anilides; D047495:PPAR gamma