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.
Ikezu
T
T
Shriners Hospitals For Crippled Children, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
Okamoto
T
T
Komatsuzaki
K
K
Matsui
T
T
Martyn
J A
JA
Nishimoto
I
I
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D001483:Base Sequence; D000242:Cyclic AMP / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D008568:Memory / Q000502:physiology; D008969:Molecular Sequence Data; D009473:Neuronal Plasticity / Q000502:physiology; D017354:Point Mutation; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid; D016192:Resting Phase, Cell Cycle; D015290:Second Messenger Systems / Q000235:genetics*; D015533:Transcriptional Activation
D016564:Amyloid beta-Protein Precursor; D011993:Recombinant Fusion Proteins; D000242:Cyclic AMP