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Thyroid Hormones Regulate ß-Amyloid Gene Splicing and Protein Secretion in Neuroblastoma Cells¹

Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, 28029 Madrid, Spain

Address all correspondence and requests for reprints to: Dr. Angel Pascual, Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Arturo Duperier 4, 28029 Madrid, Spain. E-mail: apascual{at}iib.uam.es

The ß-amyloid protein (Aß), the major component of the senile plaques found in Alzheimer brains, derives from a larger ß-amyloid precursor protein (APP). Alternative splicing of the APP gene yields three major APP messenger RNAs (mRNAs), which, in turn, give rise to the APP₇₇₀, APP₇₅₁, and APP₆₉₅ protein isoforms. In this study we examined the effects of thyroid hormone on APP expression in N2a-ß neuroblastoma cells. T₃ caused a significant increase in the APP₇₇₀ mRNA band, in detriment of the APP₆₉₅ mRNA, which was proportionately reduced. In agreement with these results, T₃ markedly altered the relative ratio of intracellular APP isoforms, increasing the amount of APP₇₇₀ and causing an equivalent reduction of the immature APP₆₉₅ isoform. In accordance with these results, the soluble APP₆₉₅-derived form was specifically reduced in the culture medium obtained from T₃-treated cells. In contrast, the increase in intracellular APP₇₇₀ was not followed by an enhanced release of soluble derivatives of this isoform. These results suggest that T₃ regulates not only APP gene splicing, but also the processing and secretion of the APP peptides. According to our results, thyroid hormone might play a role in the development of Alzheimer’s disease by modulating the intracellular and extracellular contents of APP isoforms.

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