Extracellular Zn2+ Is Essential for Amyloid β1-42-Induced Cognitive Decline in the Normal Brain and Its Rescue

Brain A beta(1-42) accumulation is considered an upstream event in pathogenesis of Alzheimer's disease. However, accumulating evidence indicates that other neurochemical changes potentiate the toxicity of this constitutively generated peptide. Here we report that the interaction of A beta(1-42) with extracellular Zn2+ is essential for in vivo rapid uptake of A beta(1-42) and Zn2+ into dentate granule cells in the normal rat hippocampus. The uptake of both A beta(1-42) and Zn2+ was blocked by CaEDTA, an extracellular Zn2+ chelator, and by Cd2+, a metal that displaces Zn2+ for A beta(1-42) binding. In vivo perforant pathway LTP was unaffected by perfusion with 1000 nM A beta(1-42) in ACSF without Zn2+. However, LTP was attenuated under preperfusion with 5 nM A beta(1-42) in ACSF containing 10 nM Zn2+, recapitulating the concentration of extracellular Zn2+, but not with 5 nM A beta(1-40) in ACSF containing 10 nM Zn2+. A beta(1-40) and Zn2+ were not taken up into dentate granule cells under these conditions, consistent with lower affinity of A beta(1-40) for Zn2+ than A beta(1-42). A beta(1-42)-induced attenuation of LTP was rescued by both CaEDTA and CdCl2, and was observed even with 500 pM A beta(1-42). A beta(1-42) injected into the dentate granule cell layer of rats induced a rapid memory disturbance that was also rescued by coinjection of CdCl2. The present study supports blocking the formation of Zn-A beta(1-42) in the extracellular compartment as an effective preventive strategy for Alzheimer's disease.