Amyloid-β is believed to contribute to the development of Alzheimer's disease, but the mechanism by which the protein damages the brain is uncertain. Now, researchers led by Dennis J. Selkoe of Harvard Medical School and Brigham & Women's Hospital, in Boston, have uncovered part of the answer (Neuron 2009, 62, 788). Working with samples from cultured cells and brain tissue, the team found that soluble amyloid-β oligomers interfere with the normal reabsorption of the excitatory neurotransmitter glutamate at synapses. The researchers believe the hydrophobic oligomers bind to membrane lipids and disrupt the structure and function of transmembrane transporters and channels that normally reabsorb glutamate from the synaptic cleft. As a result, excess glutamate accumulates near the synapses and overstimulates neurons. The excess stimulation can promote a cellular process known as long-term depression, in which synapses shrink and become less functional. If this process goes far enough, the neurons themselves can degenerate, leading to memory loss. The researchers showed that a glutamate scavenger inhibits long-term depression induced by amyloid-β, suggesting an approach for treating synaptic dysfunction in Alzheimer's disease.