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

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 3xTg-AD animals. The molecular background was examined at 8 months of age. Separate cohorts of 4- and 8-month-old 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.