Extracellular Zn²⁺ Is Essential for Amyloid β_1-42-Induced Cognitive Decline in the Normal Brain and Its Rescue

Brain Aβ_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 Aβ_1-42 with extracellular Zn²⁺ is essential for in vivo rapid uptake of Aβ_1-42 and Zn²⁺ into dentate granule cells in the normal rat hippocampus. The uptake of both Aβ_1-42 and Zn²⁺ was blocked by CaEDTA, an extracellular Zn²⁺ chelator, and by Cd²⁺, a metal that displaces Zn²⁺ for Aβ_1-42 binding. In vivo perforant pathway LTP was unaffected by perfusion with 1000 nm Aβ_1-42 in ACSF without Zn²⁺ However, LTP was attenuated under preperfusion with 5 nm Aβ_1-42 in ACSF containing 10 nm Zn²⁺, recapitulating the concentration of extracellular Zn²⁺, but not with 5 nm Aβ_1-40 in ACSF containing 10 nm Zn²⁺ Aβ_1-40 and Zn²⁺ were not taken up into dentate granule cells under these conditions, consistent with lower affinity of Aβ_1-40 for Zn²⁺ than Aβ_1-42 Aβ_1-42-induced attenuation of LTP was rescued by both CaEDTA and CdCl₂, and was observed even with 500 pm Aβ_1-42 Aβ_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-Aβ_1-42 in the extracellular compartment as an effective preventive strategy for Alzheimer's disease.SIGNIFICANCE STATEMENT Short-term memory loss occurs in normal elderly and increases in the predementia stage of Alzheimer's disease (AD). Amyloid-β_1-42 (Aβ_1-42), a possible causing peptide in AD, is bound to Zn²⁺ in the extracellular compartment in the hippocampus induced short-term memory loss in the normal rat brain, suggesting that extracellular Zn²⁺ is essential for Aβ_1-42-induced short-term memory loss. The evidence is important to find an effective preventive strategy for AD, which is blocking the formation of Zn-Aβ_1-42 in the extracellular compartment.