title: A role for synaptic zinc in activity-dependent Abeta oligomer formation and accumulation at excitatory synapses.
abstract: Soluble amyloid beta oligomers (AbetaOs) interfere with synaptic function and bind with high affinity to synapses, but the mechanism underlying AbetaO 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 AbetaO synaptic localization and enhanced oligomer formation at synaptic terminals, whereas inhibition with TTX blocked AbetaO synaptic localization and reduced AbetaO synaptic load. The zinc-binding 8-OH-quinoline clioquinol markedly reduced AbetaO 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 AbetaO synaptic 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 AbetaO 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.
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697, USA.
authors.forename: Atul
authors.initials: A
authors.lastname: Deshpande
authors.forename: Hideki
authors.initials: H
authors.lastname: Kawai
authors.forename: Raju
authors.initials: R
authors.lastname: Metherate
authors.forename: Charles G
authors.initials: CG
authors.lastname: Glabe
authors.forename: Jorge
authors.initials: J
authors.lastname: Busciglio