Exogenous 3-Iodothyronamine Rescues the Entorhinal Cortex from β-Amyloid Toxicity

Background: A novel form of thyroid hormone (TH) signaling is represented by 3-iodothyronamine (T₁AM), an endogenous TH derivative that interacts with specific molecular targets, including trace amine-associated receptor 1 (TAAR₁), and induces pro-learning and anti-amnestic effects in mice. Dysregulation of TH signaling has long been hypothesized to play a role in Alzheimer's disease (AD). In the present investigation, we explored the neuroprotective role of T₁AM in beta amyloid (Aβ)-induced synaptic and behavioral impairment, focusing on the entorhinal cortex (EC), an area that is affected early by AD pathology. Methods: Field potentials were evoked in EC layer II, and long-term potentiation (LTP) was elicited by high frequency stimulation (HFS). T₁AM (5 μM) and/or Aβ(1-42) (200 nM), were administered for 10 minutes, starting 5 minutes before HFS. Selective TAAR₁ agonist RO5166017 (250 nM) and TAAR₁ antagonist EPPTB (5 nM) were also used. The electrophysiological experiments were repeated in EC-slices taken from a mouse model of AD (mutant human amyloid precursor protein [mhAPP], J20 line). We also assessed the in vivo effects of T₁AM on EC-dependent associative memory deficits, which were detected in mhAPP mice by behavioral evaluations based on the novel-object recognition paradigm. TAAR₁ expression was determined by Western blot, whereas T₁AM and its metabolite 3-iodothyroacetic acid (TA₁) were assayed by high-performance liquid chromatography coupled to mass spectrometry. Results: We demonstrate the presence of endogenous T₁AM and TAAR₁ in the EC of wild-type and mhAPP mice. Exposure to Aβ(1-42) inhibited LTP, and T₁AM perfusion (at a concentration of 5 μM, leading to an actual concentration in the perfusion buffer ranging from 44 to 298 nM) restored it, whereas equimolar amounts of 3,5,3'-triiodo-L-thyronine (T₃) and TA₁ were ineffective. The response to T₁AM was abolished by the TAAR₁ antagonist EPPTB, whereas it was mimicked by the TAAR₁ agonist RO5166017. In the EC of APPJ20 mice, LTP could not be elicited, but it was rescued by T₁AM. The intra-cerebro-ventricular administration of T₁AM (0.89 μg/kg) also restored recognition memory that was impaired in mhAPP mice. Conclusions: Our results suggest that T₁AM and TAAR₁ are part of an endogenous system that can be modulated to prevent synaptic and behavioral deficits associated with Aβ-related toxicity.