Amyloid β-Mediated Zn(2+) Influx into Dentate Granule Cells Transiently Induces a Short-Term Cognitive Deficit

We examined an idea that short-term cognition is transiently affected by a state of confusion in Zn(2+) transport system due to a local increase in amyloid-β (Aβ) concentration. A single injection of Aβ (25 pmol) into the dentate gyrus affected dentate gyrus long-term potentiation (LTP) 1 h after the injection, but not 4 h after the injection. Simultaneously, 1-h memory of object recognition was affected when the training was performed 1 h after the injection, but not 4 h after the injection. Aβ-mediated impairments of LTP and memory were rescued in the presence of zinc chelators, suggesting that Zn(2+) is involved in Aβ action. When Aβ was injected into the dentate gyrus, intracellular Zn(2+) levels were increased only in the injected area in the dentate gyrus, suggesting that Aβ induces the influx of Zn(2+) into cells in the injected area. When Aβ was added to hippocampal slices, Aβ did not increase intracellular Zn(2+) levels in the dentate granule cell layer in ACSF without Zn(2+), but in ACSF containing Zn(2+). The increase in intracellular Zn(2+) levels was inhibited in the presence of CaEDTA, an extracellular zinc chelator, but not in the presence of CNQX, an AMPA receptor antagonist. The present study indicates that Aβ-mediated Zn(2+) influx into dentate granule cells, which may occur without AMPA receptor activation, transiently induces a short-term cognitive deficit. Extracellular Zn(2+) may play a key role for transiently Aβ-induced cognition deficits.