A Role for Synaptic Zinc in Activity-Dependent Aβ Oligomer Formation and Accumulation at Excitatory Synapses

Soluble amyloid beta oligomers (A beta Os) interfere with synaptic function and bind with high affinity to synapses, but the mechanism underlying A beta O synaptic targeting is not known. Here, we show that the accumulation of synthetic or native Alzheimer's disease (AD)-brain oligomers at synapses is regulated by synaptic activity. Electrical or chemical stimulation increased A beta O synaptic localization and enhanced oligomer formation at synaptic terminals, whereas inhibition with TTX blocked A beta O synaptic localization and reduced A beta O synaptic load. The zinc-binding 8-OH-quinoline clioquinol markedly reduced A beta O synaptic targeting, which was also reduced in brain sections of animals deficient in the synaptic vesicle zinc transporter ZnT3, indicating that vesicular zinc released during neurotransmission is critical for A beta Osynaptic targeting. Oligomers were not internalized in recycled vesicles but remained at the cell surface, where they colocalized with NR2B NMDA receptor subunits. Furthermore, NMDA antagonists blocked A beta O synaptic targeting, implicating excitatory receptor activity in oligomer formation and accumulation at synapses. In AD brains, oligomers of different size colocalized with synaptic markers in hippocampus and cortex, where oligomer synaptic accumulation correlated with synaptic loss.