Recent evidences show that peroxisome proliferator-activated receptor c (PPARc) is involved in the modulation of the amyloid-b (Ab) cascade causing Alzheimer’s disease (AD) and treatment with PPARc agonists protects against AD pathology. However, the function of PPARc steady-state activity in Ab cascade and AD pathology remains unclear. In this study, an antagonist of PPARc, GW9662, was injected into the fourth ventricle of APP/PS1 transgenic mice to inhibit PPARc activity in cerebellum. The results show that inhibition of PPARc significantly induced Ab 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 Ab. Since cerebellum is spared from significant Ab accumulation and neurotoxicity in AD patients and animal models, these findings suggest a crucial role of PPARc steady-state activity in protection of cerebellum against AD pathology.