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

Atsushi Takeda, Haruna Tamano, Munekazu Tempaku, Miku Sasaki, Chihiro Uematsu, Shoko Sato, Hiroaki Kanazawa, Zsolt L. Datki, Paul A. Adlard, Ashley I. Bush
2017 Journal of Neuroscience  
Brain A␤ 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␤ 1-42 with extracellular Zn 2ϩ is essential for in vivo rapid uptake of A␤ 1-42 and Zn 2ϩ into dentate granule cells in the normal rat hippocampus. The uptake of both A␤ 1-42 and Zn 2ϩ was blocked by CaEDTA, an
more » ... ular Zn 2ϩ chelator, and by Cd 2ϩ , a metal that displaces Zn 2ϩ for A␤ 1-42 binding. In vivo perforant pathway LTP was unaffected by perfusion with 1000 nM A␤ 1-42 in ACSF without Zn 2ϩ . However, LTP was attenuated under preperfusion with 5 nM A␤ 1-42 in ACSF containing 10 nM Zn 2ϩ , recapitulating the concentration of extracellular Zn 2ϩ , but not with 5 nM A␤ 1-40 in ACSF containing 10 nM Zn 2ϩ . A␤ 1-40 and Zn 2ϩ were not taken up into dentate granule cells under these conditions, consistent with lower affinity of A␤ 1-40 for Zn 2ϩ than A␤ 1-42 . A␤ 1-42 -induced attenuation of LTP was rescued by both CaEDTA and CdCl 2 , and was observed even with 500 pM A␤ 1-42 . A␤ 1-42 injected into the dentate granule cell layer of rats induced a rapid memory disturbance that was also rescued by coinjection of CdCl 2 . The present study supports blocking the formation of Zn-A␤ 1-42 in the extracellular compartment as an effective preventive strategy for Alzheimer's disease.
doi:10.1523/jneurosci.0954-17.2017 pmid:28652412 fatcat:lygjp4l3m5gepe67uek6mellnm