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

Abstract

Background. A novel branch of thyroid hormone (TH) signaling is represented by 3iodothyronamine (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 antiamnestic 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 (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). T 1 AM (5 µM) and/or Aβ 142 (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 (mhAPP, J20 line). We also assessed the in vivo effects of T 1 AM on EC-dependent associative memory deficits, that were detected in mhAPP mice by behavioral evaluations based on the novel-object recognition paradigm. TAAR 1 expression was determined by Western blot, while T 1 AM and its metabolite 3-iodothyroacetic acid (TA 1

Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-Like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents through the Modulation of SIRT6

“…Indeed, the results obtained after testing the ability of SG-2 to restore LTP in mhAPP mouse showed that this molecule is also able to reproduce the protective effect of T1AM against Aβ toxicity at the level of the entorhinal cortex (EC). This finding may also strengthen the role of TAAR1 as a possible drug target to ameliorate cognitive dysfunction in AD patients [35]. As a further expansion of this preliminary study, since protein homeostasis is crucial to sustain synaptic long-term plasticity and counteracting AD pathology, in future studies we will direct our attention to evaluate whether T1AM and SG-2 are also able to produce SIRT6-dependent activation of autophagy in the EC of mhAPP mice.…”

“…Previous experiments showed that mhAPP slices, perfused with ACSF enriched with 5µM T1AM, regained LTP capacity after high frequency stimulation induction protocol (HFS) [18]. Notably, in a very recent work Accorroni et al demonstrated that in the same experimental model co-administration of 5 nM EPPTB, a selective TAAR1 antagonist, was able to revert the rescuing effects of T1AM on LTP [35], suggesting a role of TAAR1 as a possible drug target to ameliorate cognitive dysfunction in AD patients. Since SG2 is a recently developed T1AM analog endowed of almost comparable TAAR1 agonist properties (EC50 SG-2 = 240 nM; EC50 T1AM = 189 nM) [36], we hypothesized that it may have a similar effect, and we decided to administer this compound in the perfusion medium at different concentrations.…”

3-Iodothyronamine and Derivatives: New Allies Against Metabolic Syndrome?

“…Furthermore, SIRT1, 3, 4, and 6 can also regulate glucose and fat homeostasis [82], thus representing a possible "entry point" for drugs simultaneously addressing metabolic syndrome and ageing. Intriguingly, T1AM showed (neuro)protective actions in several cell and rodent models, including seizure-related excitotoxic damage, altered autophagy, amyloidosis, and ischemia-reperfusion injury [61,[88][89][90][91].…”

“…It thus follows that the selective augmentation of some of T1AM actions can represent an attractive strategy for the treatment of metabolic disturbances [97]. Substantial data described in the last two decades provide compelling evidence of the action of T1AM as a multitarget modulator of metabolism and behavior in several experimental models and pathophysiological conditions [41,44,46,89,90], raising hope for increasing therapeutic option in the treatment of a wide variety of diet-and age-related diseases, such as obesity and neurodegeneration.…”

Thyroid Hormone Metabolite 3-Iodothyronamine (T1AM) Alleviates Hypoxia/Reoxygenation-Induced Cardiac Myocyte Apoptosis via Akt/FoxO1 Pathway

“…3-iodothyronamine (T1AM) is a metabolite product of the thyroid hormones (TH), which exert an opposite physiological function of classical TH such as a decrease of body temperature and metabolic rate in rodents [3]. Several studies have shown that T1AM is presumed to act on various organs and different receptors rapidly [4].…”