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 discovered in amyloid precursor APP₆₉₅. Here, we report that three FAD mutants (FAD-APPs) negatively regulated the transcriptional activity of cAMP response element (CRE) by a G(o)-dependent mechanism, but expression of wild-type APP₆₉₅ had no effect on CRE. Experiments with various Gα(s) chimeras demonstrated that Phe-APP coupled selectively to the C-terminus of Gα(o). Again, wild-type APP₆₉₅ had no effect on its C-terminus. These data indicate that FAD-APPs are gain-of-function mutants of APP₆₉₅ that negatively regulate the CRE activity through G(o). This negative transactivation of CRE is the first biochemically analyzed signal evoked by the three FAD-APPs, but not by wild-type APP₆₉₅, 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.