Inhibition of AMPA receptor trafficking at hippocampal synapses by β-amyloid oligomers: the mitochondrial contribution

• Type of Material: Article
• Authors: Yanfang Rui, Emory University; Jiaping Gu, Emory University; Kuai Yu, Emory University; Criss Hartzell Jr., Emory University; James Zheng, Emory University
• Language: English
• Date: 2010-03-26
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2010 Rui et al; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://www.molecularbrain.com/content/3/1/10
• Title of Journal or Parent Work: Molecular Brain
• ISSN: 1756-6606
• Volume: 3
• Issue: 10
• Grant/Funding Information: This work is supported in part by research grants from National Institutes of Health to JQZ (AG029596, GM083889, and GM084363) and HCH (EY014852 and GM60448), as well as by a Pilot award to JQZ from Emory Alzheimer's Disease Research Center (ADRC, P50 AG025688)
• Research Categories: Biology, Neuroscience; Biology, Molecular

Abstract

Background Synaptic defects represent a major mechanism underlying altered brain functions of patients suffering Alzheimer's disease (AD) [1-3]. An increasing body of work indicates that the oligomeric forms of β-amyloid (Aβ) molecules exert profound inhibition on synaptic functions and can cause a significant loss of neurotransmitter receptors from the postsynaptic surface, but the underlying mechanisms remain poorly understood. In this study, we investigated a potential contribution of mitochondria to Aβ inhibition of AMPA receptor (AMPAR) trafficking. Results We found that a brief exposure of hippocampal neurons to Aβ oligomers not only led to marked removal of AMPARs from postsynaptic surface but also impaired rapid AMPAR insertion during chemically-induced synaptic potentiation. We also found that Aβ oligomers exerted acute impairment of fast mitochondrial transport, as well as mitochondrial translocation into dendritic spines in response to repetitive membrane depolarization. Quantitative analyses at the single spine level showed a positive correlation between spine-mitochondria association and the surface accumulation of AMPARs. In particular, we found that spines associated with mitochondria tended to be more resistant to Aβ inhibition on AMPAR trafficking. Finally, we showed that inhibition of GSK3β alleviated Aβ impairment of mitochondrial transport, and effectively abolished Aβ-induced AMPAR loss and inhibition of AMPAR insertion at spines during cLTP. Conclusions Our findings indicate that mitochondrial association with dendritic spines may play an important role in supporting AMPAR presence on or trafficking to the postsynaptic membrane. Aβ disruption of mitochondrial trafficking could contribute to AMPAR removal and trafficking defects leading to synaptic inhibition.