Abstract
BackgroundSynaptic 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Synaptic defects represent a major mechanism underlying altered brain functions of patients suffering Alzheimer’s disease (AD) [1,2,3]
We show that soluble Ab oligomers caused acute reduction of AMPA receptor (AMPAR) on the spine surface and impaired AMPAR insertion during chemically-induced long-term potentiation (LTP)
Glycogen synthase kinase-3b (GSK3b) prevented Ab inhibition of both mitochondrial transport and AMPAR trafficking. These findings indicate that mitochondrial localization to dendritic spines may be important for AMPAR trafficking and acute Ab impairment of mitochondrial trafficking could contribute to the adverse effects of Ab on AMPARs at synapse
Summary
Synaptic defects represent a major mechanism underlying altered brain functions of patients suffering Alzheimer’s disease (AD) [1,2,3]. An increasing body of work indicates that the oligomeric forms of b-amyloid (Ab) 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. AD brains exhibit two major pathological hallmarks: extracellular senile plaques containing b-amyloid aggregates and intracellular neurofibrillary tangles consisting of hyperphosphorylated microtubule-associated tau proteins [5,6]. Aggregated Ab fibrils constitute the core of neuritic plaques and are believed to be a major culprit for neurodegeneration and subsequent cognitive abnormalities in AD patients [9,10,11]. A better understanding of Ab inhibition of synaptic functions would provide significant insights into the AD neuropathogenic process, potentially leading to better strategies for prevention and treatment of AD
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