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: Xiang-Hua Liu, Zhao Geng, Jing Yan, Ting Li, Qun Chen, Qun-Ye Zhang, Zhe-Yu Chen
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 74 Pg. 377-91 (Feb 2015) ISSN: 1095-953X [Electronic] United States
• PMID: 25484286 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• APP protein, human
• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Brain-Derived Neurotrophic Factor
• PSEN1 protein, human
• Presenilin-1
• Receptor, trkB
• Proto-Oncogene Proteins c-akt
• Dynamin I

Topics

• Alzheimer Disease (drug therapy, pathology, physiopathology, psychology)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Brain-Derived Neurotrophic Factor (metabolism)
• Cell Survival (drug effects, physiology)
• Cognition (drug effects, physiology)
• Disease Models, Animal
• Dynamin I (metabolism)
• Endocytosis (drug effects, physiology)
• Female
• HEK293 Cells
• Humans
• Male
• Mice, Transgenic
• Neurons (drug effects, pathology, physiology)
• Phosphorylation (drug effects)
• Presenilin-1 (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats, Sprague-Dawley
• Receptor, trkB (metabolism)