OBJECTIVE Pioglitazone, known as a peroxisome proliferator-activated receptor γ (PPARγ) agonist, is used to treat type 2 diabetes (T2DM).T2DM has been associated with reduced performance on numerous domains of cognitive function.Here, we investigated the effects of pioglitazone on memory im pairment in a mouse model with defects in insulin sensitivity and secretion, namely high-fat diet (HFD) streptozotocin (STZ)-in duced diabetic mice.METHODS ICR mice were fed an HFD for 4 weeks and then injected with a single low dose of STZ fol lowed by continued HFD feeding for an additional 4 weeks.The diabetic mice were orally administered with pioglitazone (9, 18mg-kg-1) for 4-5 weeks.Y-maze test and Morris water maze test (MWM) were employed for testing learning and memory.Serum glucose, serum insulin, serum triglyceride, brain amyloid peptide-β (Aβ), brain β-site amyloid precursor protein cleaving enzyme (BACE1), brain nuclear factor κB (NF-κB), brain re ceptor for advanced glycation end products (RAGE) were also tested.RESULTS The STZ/HFD diabetic mice, characterized by hyperglycemia, hyperlipemia and hypoinsulinemia, performed peody on Y-maze and MWM hence reflecting impairment of learning and memory behavior with increases of A β40/Aβ42,BACE1, NF-κB, and RAGE in brain.Treatment of PPARγ ago nist, pioglitazone, significantly reversed diabetes-induced im pairment of learning and memory behavior, which is involved in decreases of Aβ40/Aβ42 via inhibition of NF-κB, BACE1 and RAGE in brain as well as attenuation of hyperglycemia, hyper lipemia and hypoinsulinemia.CONCLUSION It is concluded that PPARγ agonist pioglitazone may be considered as potential pharmacological gents for the management of cognitive dysfunc tion in T2DM.