title: Rosiglitazone prevents amyloid-β oligomer-induced impairment of synapse formation and plasticity via increasing dendrite and spine mitochondrial number.
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.
authors.affiliation: Zhejiang Provincial Key Laboratory of Pathophysiology, Department of Physiology and Pharmacology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China.
authors.forename: Shujun
authors.initials: S
authors.lastname: Xu
authors.affiliation: Zhejiang Provincial Key Laboratory of Pathophysiology, Department of Physiology and Pharmacology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China.
authors.forename: Guilan
authors.initials: G
authors.lastname: Liu
authors.affiliation: The NO.2 Hospital of Ningbo, Ningbo, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Bao
authors.affiliation: Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Shaomin
authors.initials: S
authors.lastname: Li
authors.affiliation: Zhejiang Provincial Key Laboratory of Pathophysiology, Department of Physiology and Pharmacology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China.
authors.forename: Bangxu
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Trinity College Institute of Neuroscience, Department of Physiology, Trinity College, Dublin, Ireland.
authors.forename: Roger
authors.initials: R
authors.lastname: Anwyl
authors.affiliation: Zhejiang Provincial Key Laboratory of Pathophysiology, Department of Physiology and Pharmacology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China.
authors.forename: Qinwen
authors.initials: Q
authors.lastname: Wang
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002491:Central Nervous System Agents / Q000494:pharmacology; D003712:Dendrites / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D018697:Nootropic Agents / Q000494:pharmacology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D000077154:Rosiglitazone; D013569:Synapses / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D016229:Amyloid beta-Peptides; D000813:Anilides; D002491:Central Nervous System Agents; D018697:Nootropic Agents; D047495:PPAR gamma; D010446:Peptide Fragments; D045162:Thiazolidinediones; C075222:amyloid beta-protein (1-42); D000077154:Rosiglitazone
keywords: Alzheimer's disease; PPARγ; amyloid-β; mitochondria; rosiglitazone; synapse formation; synapse plasticity