PMID- 25484286 OWN - NLM STAT- MEDLINE DCOM- 20160106 LR - 20150209 IS - 1095-953X (Electronic) IS - 0969-9961 (Linking) VI - 74 DP - 2015 Feb TI - Blocking GSK3beta-mediated dynamin1 phosphorylation enhances BDNF-dependent TrkB endocytosis and the protective effects of BDNF in neuronal and mouse models of Alzheimer's disease. PG - 377-91 LID - S0969-9961(14)00366-0 [pii] LID - 10.1016/j.nbd.2014.11.020 [doi] AB - 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 GSK3beta, 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 (Abeta) oligomer exposure could impair BDNF-dependent TrkB endocytosis and Akt activation through enhancing GSK3beta 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 GSK3beta phosphorylating Dyn1 by using TAT-Dyn1SpS could rescue the impaired TrkB endocytosis and Akt activation upon BDNF stimuli under Abeta exposure. Finally, TAT-Dyn1SpS could facilitate BDNF-mediated neuronal survival and cognitive enhancement in mouse models of AD. These results clarified a role of GSK3beta in BDNF-dependent TrkB endocytosis and the subsequent signaling, and provided a potential new strategy by inhibiting GSK3beta-induced Dyn1 phosphorylation for AD treatment. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Liu, Xiang-Hua AU - Liu XH AD - 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. FAU - Geng, Zhao AU - Geng Z AD - 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. FAU - Yan, Jing AU - Yan J AD - 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. FAU - Li, Ting AU - Li T AD - 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. FAU - Chen, Qun AU - Chen Q AD - 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. FAU - Zhang, Qun-Ye AU - Zhang QY AD - 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. FAU - Chen, Zhe-Yu AU - Chen ZY AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20141205 PL - United States TA - Neurobiol Dis JT - Neurobiology of disease JID - 9500169 RN - 0 (APP protein, human) RN - 0 (Amyloid beta-Peptides) RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (PSEN1 protein, human) RN - 0 (Presenilin-1) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 3.5.1.50 (Dynamin I) SB - IM MH - Alzheimer Disease/drug therapy/pathology/*physiopathology/psychology MH - Amyloid beta-Peptides/metabolism MH - Amyloid beta-Protein Precursor/genetics/metabolism MH - Animals MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cell Survival/drug effects/physiology MH - Cognition/drug effects/physiology MH - Disease Models, Animal MH - Dynamin I/*metabolism MH - Endocytosis/drug effects/*physiology MH - Female MH - HEK293 Cells MH - Humans MH - Male MH - Mice, Transgenic MH - Neurons/drug effects/pathology/*physiology MH - Phosphorylation/drug effects MH - Presenilin-1/genetics/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Rats, Sprague-Dawley MH - Receptor, trkB/*metabolism OTO - NOTNLM OT - Alzheimer's disease OT - BDNF OT - Beta-amyloid OT - Dynamin1 OT - Endocytosis OT - GSK3beta EDAT- 2014/12/09 06:00 MHDA- 2016/01/07 06:00 CRDT- 2014/12/09 06:00 PHST- 2014/09/03 00:00 [received] PHST- 2014/11/26 00:00 [accepted] PHST- 2014/12/09 06:00 [entrez] PHST- 2014/12/09 06:00 [pubmed] PHST- 2016/01/07 06:00 [medline] AID - S0969-9961(14)00366-0 [pii] AID - 10.1016/j.nbd.2014.11.020 [doi] PST - ppublish SO - Neurobiol Dis. 2015 Feb;74:377-91. doi: 10.1016/j.nbd.2014.11.020. Epub 2014 Dec 5.