Type 3 Deiodinase is Induced in Brain Of Two Models Leading to Cognitive Impairment

Abstract Thyroid hormone is the regulator of brain cell maintenance, plasticity and energy production. The activation process of T4 into T3 depends on type 1 and 2 deiodinases, and type 3 (D3) inactivates T3. Several mechanisms, as oxidative stress, led by disease, imbalances D3 function. The response of D3 in the adult brain tissue in the context of different diseases is not defined. We evaluated D3 induction and its effects in the brain of two animal models. Methodology: To the metabolic-dysfunction associated steatotic liver disease (MASLD) model, male/adult Sprague Dawley rats (n=20) were assigned to control group (standard diet–2.93kcal/g) or high-fat-diet group (HFCD–4.3kcal/g). In the streptozotocin-induced Alzheimer's model (AD), adult Wistar rats (n=16) were allocated to the control group (5uL of citrate) or 5uL of streptozotocin. Sham animals were used as controls. Inflammation status, oxidative stress parameters, D3 expression and protein, as well as T3 controlled genes and endoplasmic stress and mitochondrial function were determined. Cerebral tissue from both groups had augmented carbonyl (P<0.001), reduced sulfhydryl and glutathione levels (P<0.001). D3 was induced (~30% in each group, P<0.0001) in both MASLD and AD groups trough ERK pathway, while genes controlled by T3 were diminished, suggesting diminished levels of T3 in the brain. Augmented endoplasmic reticulum stress and diminished mitochondrial biogenesis were observed in both models (P=0.001). The augmented T3 inactivation by D3 dysfunction in brain of both models results in a cascade of cell disruptions, most probably accelerating disease progression or worsening symptoms.