title: Blocking GSK3β-mediated dynamin1 phosphorylation enhances BDNF-dependent TrkB endocytosis and the protective effects of BDNF in neuronal and mouse models of Alzheimer's disease.
abstract: Endocytosis of tropomyosin related kinase B (TrkB) receptors has critical roles in brain-derived neurotrophic factor (BDNF) mediated signal transduction and biological function, however the mechanism that is governing TrkB endocytosis is still not completely understood. In this study, we showed that GSK3β, a key kinase in neuronal development and survival, could regulate TrkB endocytosis through phosphorylating dynamin1 (Dyn1) but not dynamin2 (Dyn2). Moreover, we found that beta-amyloid (Aβ) oligomer exposure could impair BDNF-dependent TrkB endocytosis and Akt activation through enhancing GSK3β activity in cultured hippocampal neurons, which suggested that BDNF-induced TrkB endocytosis and the subsequent signaling were impaired in neuronal model of Alzheimer's disease (AD). Notably, we found that inhibiting GSK3β phosphorylating Dyn1 by using TAT-Dyn1SpS could rescue the impaired TrkB endocytosis and Akt activation upon BDNF stimuli under Aβ exposure. Finally, TAT-Dyn1SpS could facilitate BDNF-mediated neuronal survival and cognitive enhancement in mouse models of AD. These results clarified a role of GSK3β in BDNF-dependent TrkB endocytosis and the subsequent signaling, and provided a potential new strategy by inhibiting GSK3β-induced Dyn1 phosphorylation for AD treatment.
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, CAS Center for Excellence in Brain Science, School of Medicine, Shandong University, Jinan, Shandong 250012, 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, CAS Center for Excellence in Brain Science, School of Medicine, Shandong University, Jinan, Shandong 250012, People's Republic of China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Geng
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, CAS Center for Excellence in Brain Science, School of Medicine, Shandong University, Jinan, Shandong 250012, 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, CAS Center for Excellence in Brain Science, School of Medicine, Shandong University, Jinan, Shandong 250012, 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, CAS Center for Excellence in Brain Science, School of Medicine, Shandong University, Jinan, Shandong 250012, People's Republic of China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Shandong University Qilu Hospital, People's Republic of China.
authors.forename: Qun-Ye
authors.initials: QY
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, CAS Center for Excellence in Brain Science, School of Medicine, Shandong University, Jinan, Shandong 250012, 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 / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D034284:Dynamin I / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D019208:Brain-Derived Neurotrophic Factor; C508853:PSEN1 protein, human; D053764:Presenilin-1; D020813:Receptor, trkB; D051057:Proto-Oncogene Proteins c-akt; D034284:Dynamin I
keywords: Alzheimer's disease; BDNF; Beta-amyloid; Dynamin1; Endocytosis; GSK3β