THYROID-HORMONES REGULATE BETA-AMYLOID GENE-SPLICING AND PROTEIN SECRETION IN NEUROBLASTOMA-CELLS

The beta-amyloid protein (A beta), the major component of the senile p laques found in Alzheimer brains, derives from a larger beta-amyloid p recursor protein (APP). Alternative splicing of the APP gene yields th ree major APP messenger RNAs (mRNAs), which, in turn, give rise to the APP(770), APP(751), and APP(695) protein isoforms. In this study we e xamined the effects of thyroid hormone on APP expression in N2a-beta n euroblastoma cells. T-3 caused a significant increase in the APP(770) mRNA band, in detriment of the APP(695) mRNA, which was proportionatel y reduced. In agreement with these results, T-3 markedly altered the r elative ratio of intracellular APP isoforms, increasing the amount of APP(770) and causing an equivalent reduction of the immature APP(695) isoform. In accordance with these results, the soluble APP(695)-derive d form was specifically reduced in the culture medium obtained from T- 3-treated cells. In contrast, the increase in intracellular APP(770) w as not followed by an enhanced release of soluble derivatives of this isoform. These results suggest that T-3 regulates not only APP gene sp licing, but also the processing and secretion of the APP peptides. Acc ording to our results, thyroid hormone might play a role in the develo pment of Alzheimer's disease by modulating the intracellular and extra cellular contents of APP isoforms.