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 (T(1)AM), an endogenous TH derivative that interacts with specific molecular targets, including trace amine-associated receptor 1 (TAAR(1)), 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 T(1)AM in beta amyloid (A beta)-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). T(1)AM (5 mu M) and/or A beta(1-42) (200 nM), were administered for 10 minutes, starting 5 minutes before HFS. Selective TAAR(1) agonist RO5166017 (250 nM) and TAAR(1) 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 T(1)AM on EC-dependent associative memory deficits, which were detected in mhAPP mice by behavioral evaluations based on the novel-object recognition paradigm. TAAR(1) expression was determined by Western blot, whereas T(1)AM and its metabolite 3-iodothyroacetic acid (TA(1)) were assayed by high-performance liquid chromatography coupled to mass spectrometry. Results: We demonstrate the presence of endogenous T(1)AM and TAAR(1) in the EC of wild-type and mhAPP mice. Exposure to A beta(1-42) inhibited LTP, and T(1)AM perfusion (at a concentration of 5 mu M, 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 (T-3) and TA(1) were ineffective. The response to T(1)AM was abolished by the TAAR(1) antagonist EPPTB, whereas it was mimicked by the TAAR(1) agonist RO5166017. In the EC of APPJ20 mice, LTP could not be elicited, but it was rescued by T(1)AM. The intra-cerebro-ventricular administration of T(1)AM (0.89 mu g/kg) also restored recognition memory that was impaired in mhAPP mice. Conclusions: Our results suggest that T(1)AM and TAAR(1) are part of an endogenous system that can be modulated to prevent synaptic and behavioral deficits associated with A beta-related toxicity.