Thyroid hormone metabolism in the cortex of male and female APP knock-in mice

Abstract

Targeting novel pathways contributing to the pathogenesis/progression of Alzheimer’s disease (AD) is crucial due to the lack of effective management and treatment modalities. Higher prevalence, progression rate and severity of AD in women than in men also establish sex as key variable in AD therapy development. Thyroid disorders, both hyper- and hypothyroidism, were found to occur with up to nine-fold higher prevalence in women compared to men. The molecular mechanisms by which thyroid dysfunction contribute to AD pathogenesis and heterogeneity remain however elusive. We therefore examined sex-related alterations in gene expression of iodothyronine deiodinase 2 (Dio2) and transthyretin (TTR) involved in the tissue metabolism and the distribution of thyroid hormones (THs), respectively, in a novel, state-of the art knock-in (KI) mouse model of AD-like amyloidosis, APPNL-G-F mice. Quantitative RT-PCR analysis revealed prominent differences in cortical Dio2 and TTR gene expression in 9-month-old male and female APPNL-G-F mice and their non KI littermates (WT). In comparison to WT male mice, the increase in Dio2 mRNA level was evident in female WT mice, while a trend toward a decrease was detected in their APPNL-G-F KI littermates. Expression in the opposite direction was observed for TTR, with a robust genotype-dependent decrease in male mice. Results are in line with well-established role of THs in the regulation of neuronal plasticity in the adult brain and suggest profound sex-biased effects of TH on Aβ induced pathology in APPNL-G-F mice.