Exogenous 3-iodothyronamine rescues the entorhinal cortex from β-amyloid toxicity

Background. A novel branch 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 our study on the entorhinal cortex (EC), an area which is early affected 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 Aβ142 (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 (mhAPP, J20 line). We also assessed the in vivo effects of T1AM on EC-dependent associative memory deficits, that were detected in mhAPP mice by behavioral evaluations based on the novel-object recognition paradigm. TAAR1 expression was determined by Western blot, while T1AM and its metabolite 3-iodothyroacetic acid (TA1) were assayed by HPLC coupled to mass spectrometry. Results. We demonstrated 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 T3 and TA1 were ineffective. The response to T1AM was abolished by TAAR1 antagonist EPPTB, while it was mimicked by TAAR1 agonist RO5166017. In the EC of APPJ20 mice, LTP could not be elicited, but it was rescued by T1AM. The i.c.v. 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.