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

DOI: 10.1186/1756-6606-3-10

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Abstract:

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.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.Alzheimer's disease (AD) often attacks aged populations and is highlighted by progressive loss of memory and cognitive abilities [4]. AD brains exhibit two major pathological hallmarks: extracellular senile plaques containing β-amyloid aggregates and intracellular neurofibrillary tangles consisting of hyperphosphorylated microtubule-associated tau proteins [5,6]. β-amyloid (Aβ) molecules are generated by proteolytic cleavage of the transmembrane β-amyloid precursor protein (APP) [7,8]. Aggregated Aβ fibrils constitute the core of neuritic plaques and are believed to be a major culprit for neurodegeneration and subsequent cognitive abnormalities in AD patients [9-11]. Recent studies, however, indicate that Aβ molecules exert adverse effects on neuronal functions

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