Soluble Oligomers of Amyloid β Protein Facilitate Hippocampal Long-Term Depression by Disrupting Neuronal Glutamate Uptake

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.