POTENTIAL CRE SUPPRESSION BY FAMILIAL ALZHEIMERS MUTANTS OF APP INDEPENDENT OF ADENYLYL-CYCLASE REGULATION

In familial Alzheimer's disease (FAD), mutations to I, F, and G have b een discovered at V642 in the neuron-specific version of the amyloid p recursor protein APP(695). It has been found that expression of each F AD mutant suppresses the transcriptional activity of the cAMP response element CRE in a G alpha(o)-dependent manner in a COS cell clone NK1 [Ikezu et al, (1996) EMBO J. 15, 2468-2475], Here we show that adenyly l cyclase (AC) inhibition is probably not the prerequisite for this pa thway, First, expression of each FAD mutant in NK1 cells had no effect on AC activity stimulated by cholera toxin and by mutationally activa ted G alpha(s), although the same expression completely repressed the stimulated CRE, Second, a transfected activating mutant of G alpha(o) inhibited CRE without detectable suppression of AC, whereas similarly transfected activating G alpha(i2) inhibited both AC and CRE, Third, F AD mutant-induced inhibition occurred for CRE activity stimulated by d ibutyryl cAMP. These data suggest that CRE suppression by FAD mutants of APP could occur independently of AC. (C) 1997 Federation of Europea n Biochemical Societies.