Amyloid β-Induced Rapid Zn Influx into Dentate Granule Cells Attenuates Maintained LTP Followed by Retrograde Amnesia.

On the basis of the evidence that amyloid β (Aβ)-induced Zn influx affects memory acquisition via attenuated long-term potentiation (LTP) induction, here we tested whether Aβ-induced Zn influx affects maintained LTP in freely moving rats, resulting in retrograde amnesia. Both maintained LTP and space memory were impaired by local injection of 250 μM ZnCl (2 μl) into the dentate gyrus, while maintained LTP was impaired by injection of either Aβ or Aβ (25 μM, 2 μl) into the dentate gyrus. Aβ-induced impairment of maintained LTP was rescued by co-injection of CaEDTA, an extracellular Zn chelator, but not by co-injection of ZnAF-2DA, an intracellular Zn chelator, suggesting that maintained LTP is impaired by Aβ via a mechanism that may involve extracellular Zn. In contrast, Aβ-induced impairments of maintained LTP and space memory were rescued by co-injection of either CaEDTA or ZnAF-2DA. Intracellular Zn in dentate granule cells was rapidly increased by Aβ injection into the dentate gyrus, but not by Aβ injection. The block of Aβ-induced increase in intracellular Zn by pretreatment with dexamethasone, a metallothionein inducer also rescued Aβ-induced impairment of maintained LTP. The present study indicates that Aβ-induced Zn influx into dentate granule cells, which more readily occurs than free Zn-induced Zn influx, attenuates maintained LTP followed by retrograde amnesia. It is likely that controlling Aβ-induced intracellular Zn dysregulation is a strategy for defending AD pathogenesis.