title: Anti-diabetes drug pioglitazone ameliorates synaptic defects in AD transgenic mice by inhibiting cyclin-dependent kinase5 activity.
abstract: Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase that is activated by the neuron specific activators p35/p39 and plays many important roles in neuronal development. However, aberrant activation of Cdk5 is believed to be associated with the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Here in the present study, enhanced Cdk5 activity was observed in mouse models of AD; whereas soluble amyloid-β oligomers (Aβ), which contribute to synaptic failures during AD pathogenesis, induced Cdk5 hyperactivation in cultured hippocampal neurons. Inhibition of Cdk5 activity by pharmacological or genetic approaches reversed dendritic spine loss caused by soluble amyloid-β oligomers (Aβ) treatment. Interestingly, we found that the anti-diabetes drug pioglitazone could inhibit Cdk5 activity by decreasing p35 protein level. More importantly, pioglitazone treatment corrected long-term potentiation (LTP) deficit caused by Aβ exposure in cultured slices and pioglitazone administration rescued impaired LTP and spatial memory in AD mouse models. Taken together, our study describes an unanticipated role of pioglitazone in alleviating AD and reveals a potential therapeutic drug for AD curing.
authors: Department of Neurology, Jiangning Hospital, Nanjing Medical University, Jiangsu, China.
authors: Jinan
authors: J
authors: Chen
authors: Department of Neurology, Jiangning Hospital, Nanjing Medical University, Jiangsu, China.
authors: Shenghua
authors: S
authors: Li
authors: Department of Neurology, Jiangning Hospital, Nanjing Medical University, Jiangsu, China.
authors: Wenshan
authors: W
authors: Sun
authors: Department of Neurology, Jiangning Hospital, Nanjing Medical University, Jiangsu, China.
authors: Junrong
authors: J
authors: Li
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000077205:Pioglitazone; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D065852:Spatial Memory / Q000187:drug effects; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D007004:Hypoglycemic Agents; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D051360:Cyclin-Dependent Kinase 5; D000077205:Pioglitazone