Extracellular Zn Is Essential for Amyloid β-Induced Cognitive Decline in the Normal Brain and Its Rescue.

Brain Aβ 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 with extracellular Zn is essential for rapid uptake of Aβ and Zn into dentate granule cells in the normal rat hippocampus. The uptake of both Aβ and Zn was blocked by CaEDTA, an extracellular Zn chelator, and by Cd, a metal that displaces Zn for Aβ binding. perforant pathway LTP was unaffected by perfusion with 1000 nm Aβ in ACSF without Zn However, LTP was attenuated under preperfusion with 5 nm Aβ in ACSF containing 10 nm Zn, recapitulating the concentration of extracellular Zn, but not with 5 nm Aβ in ACSF containing 10 nm Zn Aβ and Zn were not taken up into dentate granule cells under these conditions, consistent with lower affinity of Aβ for Zn than Aβ Aβ-induced attenuation of LTP was rescued by both CaEDTA and CdCl, and was observed even with 500 pm Aβ Aβ injected into the dentate granule cell layer of rats induced a rapid memory disturbance that was also rescued by coinjection of CdCl The present study supports blocking the formation of Zn-Aβ in the extracellular compartment as an effective preventive strategy for Alzheimer's disease. Short-term memory loss occurs in normal elderly and increases in the predementia stage of Alzheimer's disease (AD). Amyloid-β (Aβ), a possible causing peptide in AD, is bound to Zn in the extracellular compartment in the hippocampus induced short-term memory loss in the normal rat brain, suggesting that extracellular Zn is essential for Aβ-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 in the extracellular compartment.