title: Blockage of GSK3β-mediated Drp1 phosphorylation provides neuroprotection in neuronal and mouse models of Alzheimer's disease.
abstract: It is well established that mitochondrial fragmentation plays a key role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial fission is mediated by dynamin-related protein 1 (Drp1), which is highly expressed in nervous system and regulated by various posttranslational modifications including phosphorylation. We identified glycogen synthase kinase (GSK)3β-dependent Drp1 phosphorylation at Ser(40) and Ser(44), which increases Drp1 GTPase activity and its mitochondrial distribution and could induce mitochondrial fragmentation. Moreover, neurons transfected with Ser(40)Ser(44) phosphomimic Drp1 showed increased mitochondria fragmentation and were more vulnerable to amyloid-β (Aβ)-induced apoptosis. Therefore, blocking GSK3β-induced Drp1 phosphorylation may be an effective way to protect neurons from Aβ toxicity. To address this, we designed and synthesized an artificial polypeptide named TAT-Drp1-SpS, which could specifically block GSK3β-induced Drp1 phosphorylation. Our results demonstrated that TAT-Drp1-SpS treatment could significantly reduce Aβ-induced neuronal apoptosis in cultured neurons. Notably, TAT-Drp1-SpS administration in hippocampus Cornu Ammonis 1 (CA1) region significantly reduced Aβ burden and rescued the memory deficits in AD transgenic mice. Although Aβ has multiple targets to exert its neurotoxicity, our findings suggested that GSK3β-induced mitochondrial fragmentation was, at least partially, mediated by Aβ toxicity and contribute to the pathogenesis of AD. Taken together, GSK3β-induced Drp1 phosphorylation provides a novel mechanism for mitochondrial fragmentation in AD, and our findings suggested a novel therapeutic strategy for AD.
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Xiang-Hua
authors.initials: XH
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Ming-Zhi
authors.initials: MZ
authors.lastname: Han
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Yu-Meng
authors.initials: YM
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Xu-Lu
authors.initials: XL
authors.lastname: Sun
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Nuo
authors.initials: N
authors.lastname: Yu
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Su
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China. Electronic address: zheyuchen@sdu.edu.cn.
authors.forename: Zhe-Yu
authors.initials: ZY
authors.lastname: Chen
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology* / Q000517:prevention & control* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D034281:Dynamins / Q000378:metabolism*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology; D008297:Male; D008568:Memory; D008822:Mice, Transgenic; D063154:Mitochondrial Dynamics / Q000235:genetics; D009474:Neurons / Q000648:ultrastructure; D010766:Phosphorylation / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C486391:Dnm1l protein, mouse; D034281:Dynamins
keywords: APP/PS1 transgenic mice; Alzheimer's disease; Amyloid-β; Drp1; GSK3β; Learning and memory; Mitochondrial fragmentation; Neuronal apoptosis; TAT-like polypeptide