P2–054: Lack of phosphorylation of the amyloid precursor protein on Thr668 residue increases the gamma–cleavage of the protein

tau and the production of A . Results: CHO cells and rat cultured neurons expressing human APP695 were treated with a nontoxic 5 mM concentration of LiCl. Nuclear translocation of -catenin in both cellular models, as well as a decrease in tau phosphorylation in neurons was observed. In CHO cells, 5 mM LiCl increased the amount of extracellular A and C-terminal -cleaved fragment of APP ( CTF). Increase in the -cleavage did not result from a modification of the cellular distribution of APP and BACE1. Interestingly, the -secretase activity of CHO cells was increased in the presence of LiCl. In primary culture of rat cortical neurons, GSK3 inhibition by LiCl induced a similar increase in both extracellular A and CTF. An increase in the amount of BACE1 protein was also observed. Since LiCl is not a specific inhibitor of GSK3 but can display a number of other activities, a more selective GSK3 inhibitor (SB415286) was utilized. At a nontoxic 25 M concentration, SB415286 induced nuclear translocation of -catenin and slightly reduced the production of extracellular A . LiCl and SB415286 had cumulative effects on extracellular A production, indicating that LiCl-mediated increase in A production is not related to GSK3 inhibition. Conclusions: Taken together, these results demonstrate that LiCl increases the production of extracellular A by increasing the -cleavage of APP. LiCl increases the production of A , independently of its inhibition of GSK3.