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

• Published in: Molecular brain 2010-03, Vol.3, p.10
• Main Authors: Rui, Yanfang, Gu, Jiaping, Yu, Kuai, Hartzell, H Criss, Zheng, James Q
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyloid beta-protein; Cell receptors; Complications and side effects; Experiments; Glucose; Health aspects; Mitochondria; Neurology; Neurons; Physiological aspects; Postsynaptic potentials; Proteins; Rodents
• ISSN: 1756-6606; 1756-6606
• DOI: 10.1186/1756-6606-3-10

Background Synaptic defects represent a major mechanism underlying altered brain functions of patients suffering Alzheimer's disease (AD) 123. An increasing body of work indicates that the oligomeric forms of [beta]-amyloid (A[beta]) 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 A[beta] inhibition of AMPA receptor (AMPAR) trafficking. Results We found that a brief exposure of hippocampal neurons to A[beta] 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 A[beta] 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 A[beta] inhibition on AMPAR trafficking. Finally, we showed that inhibition of GSK3[beta] alleviated A[beta] impairment of mitochondrial transport, and effectively abolished A[beta]-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. A[beta] disruption of mitochondrial trafficking could contribute to AMPAR removal and trafficking defects leading to synaptic inhibition.