Rosiglitazone Prevents Amyloid-β Oligomer-Induced Impairment of Synapse Formation and Plasticity via Increasing Dendrite and Spine Mitochondrial Number

Article type: Research Article

Authors: Xu, Shujun^a | Liu, Guilan^a | Bao, Xiaoming^b | Wu, Jie^c | Li, Shaomin^d | Zheng, Bangxu^a | Anwyl, Roger^e | Wang, Qinwen^{a; *}

Affiliations: [a] Zhejiang Provincial Key Laboratory of Pathophysiology, Department of Physiology and Pharmacology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China | [b] The NO.2 Hospital of Ningbo, Ningbo, China | [c] Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA | [d] Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA | [e] Trinity College Institute of Neuroscience, Department of Physiology, Trinity College, Dublin, Ireland

Correspondence: [*] Correspondence to: Shujun Xu and Qinwen Wang, Zhejiang Provincial Key Laboratory of Pathophysiology, Department of Physiology and Pharmacology, School of Medicine, Ningbo University, Ningbo 315211, Zhejiang, China. Tel.: +86 574 8760 9594; Fax: +86 574 8760 8638; E-mails: xushujun@nbu.edu.cn; wangqingwen@nbu.edu.cn.

Abstract: Rosiglitazone 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.

Keywords: Alzheimer's disease, amyloid-β, mitochondria, PPARγ, rosiglitazone, synapse formation, synapse plasticity

DOI: 10.3233/JAD-130680

Journal: Journal of Alzheimer's Disease, vol. 39, no. 2, pp. 239-251, 2014