Human amyloid-beta(1-40) (A beta(1-40)) and rat A beta(1-42) have lower affinity for extracellular Zn2+ than human A(beta(1-42). Here we report extracellular Zn2+-independent attenuation of dentate gyrus long-term potentiation (LTP) by human A beta(1-40) and rat A beta(1-42). On the basis of the data that dentate gyrus LTP is extracellular Zn2+-dependently attenuated after local injection of human A beta(1-42) (25 pmol, 1 mu l) into the dentate gyrus, which increases intracellular Zn2+ in the dentate gyrus, the toxicity of human A beta(1-40) and rat A beta(1-42) was compared in the in vivo system with human A beta(1-42). Dentate gyrus LTP was attenuated after injection of human A beta(1-40) and rat A beta(1-42) (25 pmol, 1 mu l) into the dentate gyrus, which did not increase intracellular Zn2+ in the dentate gyrus. The attenuated LTP was not rescued by co-injection of CaEDTA, an extracellular Zn2+ chelator. The present study suggests that human A beta(1-40) and rat A beta(1-42) affect cognitive activity via extracellular Zn2+-independent mechanism at low micromolar concentration. (C) 2019 Elsevier Inc. All rights reserved.