NEGATIVE TRANSACTIVATION OF CAMP RESPONSE ELEMENT BY FAMILIAL ALZHEIMERS 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,v ered in amyloid precursor APP(695). Here, we report that three FAD mut ants (FAD-APPs) negatively regulated the transcriptional activity of c AMP response element (CRE) by a G(0)-dependent mechanism, but expressi on 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-funct ion mutants of APP(695) that negatively regulate the CRE activity thro ugh G(0). This negative transactivation of CRE is the first biochemica lly 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 cons titutive CRE suppression by FAD-APPs, which is potentially relevant to synaptic malplasticity or memory disorders.