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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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 wildtype APP695 had no effect on CRE. Experiments with various Galpha(s) chimeras demonstrated that Phe-APP coupled selectively to the C-terminus of Galpha(0). 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.[1]


  1. Negative transactivation of cAMP response element by familial Alzheimer's mutants of APP. Ikezu, T., Okamoto, T., Komatsuzaki, K., Matsui, T., Martyn, J.A., Nishimoto, I. EMBO J. (1996) [Pubmed]
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