Thyroid hormone regulation of APP (β-amyloid precursor protein) gene expression in brain and brain cultured cells

We have previously shown that the thyroid hormone triiodothyronine negatively regulates the transcriptional activity of the β-amyloid precursor protein gene (APP) in cultured murine neuroblastoma cells, by a mechanism that involves binding of the nuclear thyroid hormone receptor (TR) to DNA sequences located within the first exon of the gene. In this report we present results showing that the thyroid hormones also repress the expression of APP in human neuroblastoma cells and in primary cultures of rat neurons. In addition, and in agreement with the results obtained in cultured cells, APP messenger RNA and protein levels are significantly higher in the brain of hypothyroid rats and mice, and also in Alzheimer-related brain regions dissected from KO mice lacking TRs. These results show that binding of the thyroid hormones to their nuclear receptors mediate their repressive effect on APP gene expression in vivo.

► Thyroid hormones repress APP gene expression in primary cultures of rat neurons. ► APP levels are increased in the brain of hypothyroid mice and rats. ► Hippocampus and cortex, but not cerebellum, are affected. ► Thyroid hormone receptors deficient mice also exhibit increased brain APP levels. ► Thyroid hormones might play a neuroprotective role in Alzheimer’s disease.