Metabolic insights into the 3xTg-AD Alzheimer model mice: Unraveling the hypothalamic-pituitary-thyroid axis and beyond

Szabó, Adrienn and Farkas, Szidónia and Kádár, Andrea and Török, Bibiána and Fazekas, Csilla Lea and Sipos, Eszter and Bánrévi, Krisztina and Correia, Pedro and Chaves, Tiago and Kovács, Tamás and Penksza, Veronika and Fekete, Csaba and Zelena, Dóra (2026) Metabolic insights into the 3xTg-AD Alzheimer model mice: Unraveling the hypothalamic-pituitary-thyroid axis and beyond. PSYCHONEUROENDOCRINOLOGY, 188. ISSN 0306-4530

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Abstract

The 3xTg-AD mouse model is widely used to study the pathomechanisms of Alzheimer’s disease (AD) and to test potential therapies. During food-motivated cognitive tasks, however, increased food-directed behavior was observed in these animals, raising the possibility that metabolic factors may influence task performance. This prompted us to investigate the metabolic background of AD, with a focus on the hypothalamic-pituitary-thyroid (HPT) axis. Testing of food-motivated behavior (single pellet reaching, radial arm maze, staircase, and operant conditioning tests) started at 6 months of age in male mice and confirmed increased motivation for food in 3xTgAD animals. The molecular background was examined at 8 months of age. Separate cohorts of 4- and 8-monthold male mice underwent metabolic measurements. Transgenic mice showed increased food and water intake, reduced fat mass, elevated lean mass, and a stable respiratory exchange ratio (RER), in contrast to the age-related decline in RER observed in controls. Free T4 levels were higher in 3xTg-AD than control animals, and molecular profiling revealed elevated thyrotropin-releasing hormone (TRH) and thyroid hormone-activating deiodinases DIO1 and DIO2 mRNA, alongside reduced expression of the thyroid hormone receptor beta 2 (THRB2) in the paraventricular nucleus (PVN) and pituitary. Expression levels of key appetite-regulating neuropeptides, including pro-opiomelanocortin (POMC), neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART), and agouti-related peptide (AgRP) were significantly lower in 3xTg-AD mice. These findings indicate early alterations in energy homeostasis and HPT axis-related signaling in 3xTg-AD mice that may be associated with increased food-seeking behavior. Our data provide evidence for metabolic and neuroendocrine changes that accompany the behavioral phenotype of this model.

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