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Alzheimer’s disease (AD) is a slow-onset neurodegenerative disorder and the essentially pathological hallmarks are linked with amyloid beta peptides (Abeta)and gamma-secretase. Recently, copper and zinc ions were found to be present with a high concentration in the Abeta depositions and the synaptic cleft. However, how Cu2+ and Zn2+ regulate the production of Abeta remains largely unknown.


In the present study, we demonstrate in cell-free and cell-based assays that Cu2+ and Zn2+ regulate the production of the Abeta by distinct molecular mechanisms affecting the gamma-secretase processing of the amyloid beta precursor protein (APP) C-terminal fragment APP-C99. The IC50 for Cu2+ and Zn2+ in the purified gamma-secretase assay were found to be 1 microM and 15 microM, respectively. Cu2+ was verified to directly bind the complex of gamma-secretase rather than the substrate APP-C99. Conversely,Zn2+ was demonstrated to interfere with histidine residues H6, H13 and H14 of APP-C99 to induce the SDS-resistance dimer of APP-C99 and reduce the production of Abeta. Additionally, we observed that Zn2+ could elevate the ratio between Abeta43 and Abeta40. Considering that Abeta43 has recently been discovered to be a novel toxic Abeta peptide in the progress of AD, our results seem to suggest that Zn2+ is a risk fact for the genesis of AD. Taken together, these results have not only verify the regulatory effect and the underlying mechanism of Cu2+ and Zn2+ on the production of Abeta, but also provide a molecular mechanism to explain the generation of various length of Abeta by gamma-secretase. The above work has been online published in Journal of Biological Chemistry.

Copyright: 2013 Young Scientist Laboratory of Shanghai Jiaotong University       Technical Support: Shanghai Yi-chao Information Technology Co., Ltd.