Thyroid Hormone Regulates Endogenous Amyloid-β Precursor Protein Gene Expression and Processing in Both In Vitro and In Vivo Models

Abstract

Thyroid hormone negatively regulates the amyloid-beta precursor protein (APP) gene in thyroid hormone receptor (TR)-transfected neuroblastoma cells. A negative thyroid hormone response element (nTRE) that mediates this regulation has been identified in the first exon of the APP gene. We demonstrate in an in vivo system that expression of APP mRNA, APP protein, and APP secretase cleavage products in mouse brain is influenced by thyroid status. Adult female mice were made hyperthyroid or hypothyroid for 3 weeks and compared to euthyroid mice. APP gene product expression was increased in hypothyroid mouse brain and reduced in hyperthyroid mouse brain, when compared to euthyroid controls. We observed similar effects of thyroid hormone on endogenous APP gene expression in human neuroblastoma cells. The incidence of hypothyroidism increases with age, and localized hypothyroidism of central nervous system has been reported in some patients with Alzheimer's disease (AD). Reduced action of thyroid hormone on the APP gene may contribute to AD pathology by increasing APP expression and the levels of processed APP products. These findings may be an underlying mechanism contributing to the association of hypothyroidism with AD in the elderly, as well as identifying a potential therapeutic target. Pharmacologic supplementation of thyroid hormone, or its analogs, may reduce APP gene expression and beta amyloid peptide accumulation.

Cognitive Function, <b><i>APOE</i></b> Gene Polymorphisms, and Thyroid Status Associations in Postmenopausal Women in Poland

“…Elderly adults with both hyperthyroidism and AD had more neocortical neuritic plaques and neurofibrillary tangles than participants with either condition alone [31]. The probable role of thyroid hormone in AD pathophysiology was established, mainly in the area of Aβ plaque accumulation [57]. The use of thyroid hormone replacement therapy was demonstrated to be associated with an increased rate of progression to AD diagnosis.…”

Thyroid Hormones Are Associated with Poorer Cognition in Mild Cognitive Impairment

“…They also decrease hyperphosphorylation of the tau protein, which accumulates in neurofibrillary tangles [17, 18] and is associated with cognitive impairment [19]. TH have been observed to decrease amyloid precursor protein expression [20], and estrogen may prevent Aβ accumulation through effects on amyloid precursor protein processing [21]. Cortisol, in contrast, has been shown to increase levels of Aβ 40 and Aβ 42 and accelerate the development of neurofibrillary tangles in the brain [22].…”

Thyroid Hormone Enhances Neurite Outgrowth in Neuroscreen 1 Cells

“…However, it is not clear what mechanisms are impaired that lead to this outcome. One possible explanation is the finding that thyroid hormone down-regulates the expression of the APP gene [35][36][37]. This is a critical and significant finding considering that the accumulation of Aβ results from high expression levels of APP [38,39].…”