Amyloid [beta]-Mediated Zn.sup.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.sup.2+ transport system due to a local increase in amyloid-[beta] (A[beta]) concentration. A single injection of A[beta] (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. A[beta]-mediated impairments of LTP and memory were rescued in the presence of zinc chelators, suggesting that Zn.sup.2+ is involved in A[beta] action. When A[beta] was injected into the dentate gyrus, intracellular Zn.sup.2+ levels were increased only in the injected area in the dentate gyrus, suggesting that A[beta] induces the influx of Zn.sup.2+ into cells in the injected area. When A[beta] was added to hippocampal slices, A[beta] did not increase intracellular Zn.sup.2+ levels in the dentate granule cell layer in ACSF without Zn.sup.2+, but in ACSF containing Zn.sup.2+ . The increase in intracellular Zn.sup.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 A[beta]-mediated Zn.sup.2+ influx into dentate granule cells, which may occur without AMPA receptor activation, transiently induces a short-term cognitive deficit. Extracellular Zn.sup.2+ may play a key role for transiently A[beta]-induced cognition deficits.