Journal
NEURON
Volume 62, Issue 6, Pages 788-801Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2009.05.012
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Funding
- NIH [AG027443]
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In Alzheimer's disease (AD), the impairment of declarative memory coincides with the accumulation of extracellular amyloid-beta protein (A beta) and intraneuronal tau aggregates. Dementia severity correlates with decreased synapse density in hippocampus; and cortex. Although numerous studies show that soluble A beta oligomers inhibit hippocampal long-term potentiation, their role in long-term synaptic depression (LTD) remains unclear. Here, we report that soluble A beta oligomers from several sources (synthetic, cell culture, human brain extracts) facilitated electrically evoked LTD in the CA1 region. A beta-enhanced LTD was mediated by mGluR or NMDAR activity. Both forms of LTD were prevented by an extracellular glutamate scavenger system. A beta-facilitated LTD was mimicked by the glutamate reuptake inhibitor TBOA, including a shared dependence on extracellular calcium levels and activation of PP2B and GSK-3 signaling. In accord, synaptic glutamate uptake was significantly decreased by soluble A beta. We conclude that soluble A beta oligomers perturb synaptic plasticity by altering glutamate recycling at the synapse and promoting synapse depression.
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