• Shujun Xu, Guilan Liu, Xiaoming Bao, Jie Wu, Shaomin Li, Bangxu Zheng, Roger Anwyl, and Qinwen Wang.
• Zhejiang Provincial Key Laboratory of Pathophysiology, Department of Physiology and Pharmacology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China.
• J. Alzheimers Dis. 2014 Jan 1;39(2):239-51.

AbstractRosiglitazone has been known to attenuate neurodegeneration in Alzheimer's disease (AD), but the underlying mechanisms remain to be fully elucidated. In this study, living-cell image, immunocytochemistry, and electrophysiology were used to examine the effects of soluble amyloid-β protein (Aβ) oligomers and rosiglitazone on the synapse formation, plasticity, and mitochondrial distribution in cultured neurons. Incubation of hippocampal cultures with amyloid-β (Aβ)42 oligomers (0.5 μM) for 3 h significantly decreased dendritic filopodium and synapse density. Pretreatment with rosiglitazone (0.5-5 μM) for 24 h prevented the Aβ42-induced loss of dendritic filopodium and synapse in a dose-dependent manner. However, neither Aβ42 oligomer nor rosiglitazone has a significant effect on the velocity and length of dendritic filopodia. Electrophysiological recording showed that acute exposure of slices with 0.5 μM Aβ42 oligomers impaired hippocampal long-term potentiation (LTP). Pre-incubation of hippocampal slices with rosiglitazone significantly attenuated the Aβ42-induced LTP deficit, which depended on rosiglitazone concentrations (1-5 μM) and pretreatment period (1-5 h). The beneficial effects of rosiglitazone were abolished by the peroxisome proliferator-activated receptor gamma (PPARγ) specific antagonist, GW9662. Moreover, the mitochondrial numbers in the dendrite and spine were decreased by Aβ42 oligomers, which can be prevented by rosiglitazone. In conclusion, our data suggested that rosiglitazone prevents Aβ42 oligomers-induced impairment via increasing mitochondrial numbers in the dendrite and spine, improving synapse formation and plasticity. This process is most likely through the PPARγ-dependent pathway and in concentration and time dependent manners. The study provides novel insights into the mechanisms for the protective effects of rosiglitzone on AD.

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