Potential CRE suppression by familial Alzheimer's mutants of APP independent of adenylyl cyclase regulation

In familial Alzheimer's disease (FAD), mutations to I, F, and G have been discovered at V642 in the neuron-specific version of the amyloid precursor protein APP695. It has been found that expression of each FAD 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 adenylyl cyclase (AC) inhibition is probably not the prerequisite for this pathway. First, expression of each FAD mutant in NK1 cells had no effect on AC activity stimulated by cholera toxin and by mutationally activated 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, FAD mutant-induced inhibition occurred for CRE activity stimulated by dibutyryl cAMP. These data suggest that CRE suppression by FAD mutants of APP could occur independently of AC.