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

Tsuneya Ikezu, Takashi Okamoto, Katsumi Komatsuzaki, Takashi Matsui, J. A. Jeevendra Martyn, Ikuo Nishimoto

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2468-2475
Number of pages8
JournalEMBO Journal
Volume15
Issue number10
DOIs
StatePublished - 1996

Keywords

  • Amyloid precursor protein
  • cAMP response element
  • Familial Alzheimer's disease
  • G(o)-dependent mechanism
  • Memory formation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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