3-iodothyronamine ameliorates ischemia-dependent synaptic dysfunction in a mouse model of Alzheimer's disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a slowly progressive cognitive decline. In particular, vascular pathologies, such as hypertension, ischemic stroke, type II diabetes and atherosclerosis, have been demonstrated to contribute to AD pathogenesis, through the increase of amyloid-β precursor protein (APP) and β-amyloid (Aβ) cleavage. On the other hand, a specific susceptibility to ischemia has been found in brains of APP overexpressing mice, further strengthening the link between ischemia and AD. This evidence suggests that the ischemic damage and Aβ overproduction can have a synergic effect in promoting dementia. In addition, a recent study demonstrated that inflammatory pathways linked to Aβ contribute to the ischemia-induced synaptic dysfunction in the entorhinal cortex (EC), an area involved in cognitive processes and early affected by AD. Therefore, it is important to identify neuroprotective compounds able to ameliorate synaptic dysfunction due to Aβ and triggered by ischemia. Among all the neuroendocrine and neuromodulatory systems that can influence neuronal function, thyroid hormones (TH) appear to be worth investigating as they are involved both in AD and vascular dysfunctions. In fact, TH deficiency is known to contribute to AD and to be a risk factor for stroke. Moreover, TH have a complex metabolism and their central effect can be modulated by a composite network of metabolites. In particular, a novel endogenous putative TH derivative, 3-iodothyronamine (T1AM), has been demonstrated to induce a pro-learning effect when administered intracerebroventricularly in mice, stimulating the acquisition of memory. The T1AM is a biogenic amine with a chemical structure very similar to that of 3,5,3’-triiodothyronine (T3), from which it is supposed to derive. Furthermore, T1AM is widely distributed in mouse tissues with high concentrations found in liver, brain and muscle. In order to investigate T1AM effect on the ischemia-dependent synaptic dysfunction in an Aβ-enriched environment, we took advantage of mice overexpressing a human mutant form of amyloid-β precursor protein (mhAPP) gene bearing Swedish and Indiana mutations linked to familial AD (K670N/M671L, V717F). The EC synaptic function was evaluated in horizontal brain slices and field excitatory post-synaptic potentials (fEPSP) were recorded placing the stimulating and the recording electrode in superficial layer II. After 10 min of baseline recordings, in which slices were perfused with regular oxygenated artificial cerebrospinal fluid (ACSF), slices were exposed to 10 min of oxygen-glucose deprivation (OGD, with deoxygenated ACSF and glucose substituted by D-mannitol at equimolar concentration) and then recovered for 50 min with the reintroduction of regular oxygenated-ACSF. The T1AM compound (5 µM) was perfused for 10 min during the application of OGD. The relative % amplitude with respect to the baseline was considered as the main parameter of fEPSP. After investigating T1AM effect against ischemia-dependent synaptic dysfunction, we focused on T1AM main molecular target, the trace amine-associated receptor 1 (TAAR1). To this aim, we used either an antagonist (EPPTB) or an agonist (RO5166017) of TAAR1. In agreement with previous findings, the long-lasting synaptic depression induced by OGD was enhanced in EC slices from mhAPP mice with respect to the WT. However, T1AM acute perfusion during OGD was able to ameliorate synaptic dysfunction either in WT or mhAPP slices. Moreover, a similar protective effect was achieved by the perfusion of RO5166017 (250 nM). Conversely, the protective effect of T1AM against OGD-induced synaptic depression was abolished in the presence of EPPTB (5 nM). Our results suggest that T1AM can ameliorate the ischemia-dependent synaptic dysfunction either in WT or in an amyloid-enriched environment and that TAAR1 can be involved in this T1AM-mediated neuroprotection