Difference in ability for extracellular Zn²⁺ influx between human and rat amyloid β_1-42 and its significance

The accumulation of amyloid-β_1-42 (Aβ_1-42), a constituively-generated peptide, in the brain is considered an upstream event in pathogenesis of Alzheimer's disease. Aβ_1-42-induced pathophysiology has been extensively studied in experimental mice and rats. However, neurotoxicity of murine Aβ_1-42 is much less understood than human Aβ_1-42. Here we report difference in ability for extracellular Zn²⁺ influx into dentate granule cells of rats between human and rat Aβ_1-42 and its significance. Human Aβ_1-42 rapidly increased intracellular Zn²⁺, which was determined with intracellular ZnAF-2, in dentate granule cells, 5 min after injection of Aβ_1-42 (25 μM, 1 μl) into the dentate gyrus, while rat Aβ_1-42 did not increase intracellular Zn²⁺. In vivo perforant pathway LTP was attenuated under pre-perfusion with 5 nM human Aβ_1-42 in artificial cerebrospinal fluid (ACSF) containing 10 nM Zn²⁺, recapitulating the concentration of extracellular Zn²⁺, but not with 5 nM rat Aβ_1-42 in ACSF containing 10 nM Zn²⁺. The present study suggests that rat Aβ_1-42 has lower affinity for extracellular Zn²⁺ than human Aβ_1-42 and does not capture Zn²⁺ in the extracellular compartment, resulting in no significant effect on cognitive activity of rat even in the range of very low nanomolar concentrations of endogenous Aβ_1-42.