Triiodothyronine Treatment Reverses Depression-Like Behavior in a Triple-Transgenic Animal Model of Alzheimer’s Disease.

Abstract Introduction: Alzheimer disease’s (AD) is a neurodegenerative disorder and it is known that the central nervous system (CNS) is an important target of thyroid hormones (TH). Moreover, an inverse association between serum triiodothyronine (T3) levels and the risk of AD was reported. Aim: To evaluate the effects of T3 treatment on the depression-like behavior observed in male transgenic 3xTg-AD mice. Main methods: Animals were divided into 2 groups, one group received daily intraperitoneal injections of L-T3 (T3 group), and the other received an equivalent volume of 0.9% saline (Control group). The experimental protocol lasted 21 days, and behavioral tests were conducted on days 15-19. At the conclusion of the experiment, the TH profile and hippocampal gene expression were evaluated. Key findings: It was observed that the T3-treated group presented significantly increased serum T3 and decreased thyroxine (T4) levels. When compared to control hippocampal samples, the T3 group exhibited attenuated glycogen synthase kinase-3 (GSK3), metalloproteinase 10 (ADAM10), amyloid-beta precursor-protein (APP), serotonin transporter (SERT), 5HT1a receptor, monocarboxylate transporter 8 (MCT8) and bone morphogenetic protein 7 (BMP-7) gene expression levels and augmented superoxide dismutase 2 (SOD2) and Hairless gene expression levels. Additionally, T3-treated animals displayed reduced immobility time in both the tail suspension and forced swim tests, and in the latter presented a higher latency time when compared to the control group. Significance: Taken together, our results demonstrate that in an AD mouse model, T3 supplementation promotes improvements in depression-like behavior, likely through the modulation of the serotonergic pathway, and also attenuated disease progression.