Pioglitazone prevents tau oligomerization

Tau aggregation and amyloid beta protein (A beta) deposition are the main causes of Alzheimer's disease (AD). Peroxisome proliferator-activated receptor gamma (PPAR gamma) activation modulates A beta production. To test whether the PPAR gamma agonist pioglitazone (PIO) is also effective in preventing tau aggregation in AD, we used a cellular model in which wild-type tau protein (4R0N) is overexpressed (M1C cells) (Hamano et al., 2012) as well as primary neuronal cultures. PIO reduced both phosphorylated and total tau levels, and inactivated glycogen synthase kinase 3 beta, a major tau kinase, associated with activation of Akt. In addition, PIO decreased cleaved caspase3 and C-terminal truncated tau species by caspase, which is expected to decrease tau aggregation. A fractionation study showed that PIO reduced high molecular-weight (120 kDa), oligomeric tau species in Tris Insoluble, sarkosyl-soluble fractions. Tau decrease was reversed by adding GW9662, a PPAR gamma antagonist. Together, our current results support the idea that PPAR gamma agonists may be useful therapeutic agents for AD. (C) 2016 Elsevier Inc. All rights reserved.