Recent evidences show that peroxisome proliferator-activated receptor gamma (PPAR gamma) is involved in the modulation of the amyloid-beta (A beta) cascade causing Alzheimer's disease (AD) and treatment with PPAR gamma agonists protects against AD pathology. However, the function of PPARs gamma, steady-state activity in A beta cascade and AD pathology remains unclear. In this study, an antagonist of PPAR gamma, GW9662, was injected into the fourth ventricle of APP/PS1 transgenic mice to inhibit PPAR gamma activity in cerebellum. The results show that inhibition of PPAR gamma significantly induced A beta 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 A beta. Since cerebellum is spared front significant A beta accumulation and neurotoxicity in AD patients and animal models, these findings suggest a crucial role of PPAR gamma steady-state activity in protection of cerebellum against AD pathology. (C) 2009 Elsevier Inc. All rights reserved.