Negative transactivation of cAMP response element by familial Alzheimer's mutants of APP

In familial Alzheimer's disease (FAD), missense point mutations V642I/F/G, which co-segregate, with the disease phenotype, have been disco,vered in amyloid precursor APP(695). Here, we report that three FAD mutants (FAD-APPs) negatively regulated the transcriptional activity of cAMP response element (CRE) by a G(0)-dependent mechanism, but expression of wildtype APP(695) had no effect on CRE. Experiments with various G alpha(s) chimeras demonstrated that Phe-APP coupled selectively to the C-terminus of G alpha(0). Again, wild-type APP(695) had no effect on its C-terminus, These data indicate that FAD-APPs are gain-of-function mutants of APP(695) that negatively regulate the CRE activity through G(0). This negative transactivation of CRE is the first biochemically analyzed signal evoked by the three FAD-APPs, but not by wild-type APP(695), in a whole-cell system, We discuss the significance of constitutive CRE suppression by FAD-APPs, which is potentially relevant to synaptic malplasticity or memory disorders.