Abstract
3-iodothyronamine (T1AM) and the recently developed analog SG-2 are rapidly emerging as promising multi-target neuroprotective ligands able to reprogram lipid metabolism and to produce memory enhancement in mice. To elucidate the molecular mechanisms underlying the multi-target effects of these novel drug candidates, here we investigated whether the modulation of SIRT6, known to play a key role in reprogramming energy metabolism, might also drive the activation of clearing pathways, such as autophagy and ubiquitine-proteasome (UP), as further mechanisms against neurodegeneration. We show that both T1AM and SG-2 increase autophagy in U87MG cells by inducing the expression of SIRT6, which suppresses Akt activity thus leading to mTOR inhibition. This effect was concomitant with down-regulation of autophagy-related genes, including Hif1α, p53 and mTOR. Remarkably, when mTOR was inhibited a concomitant activation of autophagy and UP took place in U87MG cells. Since both compounds activate autophagy, which is known to sustain long term potentiation (LTP) in the entorhinal cortex (EC) and counteracting AD pathology, further electrophysiological studies were carried out in a transgenic mouse model of AD. We found that SG-2 was able to rescue LTP with an efficacy comparable to T1AM, further underlying its potential as a novel pleiotropic agent for neurodegenerative disorders treatment.
Highlights
Growing evidence suggests the presence of a strong association between obesity and neurodegeneration [1,2,3]
In the present study, using the quantitative polymerase chain reaction assay we found that sirtuin 6 (SIRT6) was highly upregulated in U87MG cells treated for 24 h with (1 μM) T1AM, SG-1 or SG-2 (Figure 2a)
We found that 3-iodothyronamine (T1AM), an endogenous component of the thyroid endocrine system originally identified as a potent trace amine associated receptor 1
Summary
Growing evidence suggests the presence of a strong association between obesity and neurodegeneration [1,2,3]. Evidence was provided that 3-iodothyronamine (T1AM), an endogenous component of the thyroid endocrine system [9,10], reprogrammed altered metabolism when exogenously administered to obese mice at pharmacological doses (10 and 25 mg/kg) [11] This effect was based on the activation of SIRT6-mediated pathways [12], which in turn actively rescued fatty acid and glucose metabolism. The present investigation was further motivated by recent findings, which indicate that the two major clearing pathways, namely autophagy and ubiquitine proteasome (UP), considered as independent for long time, converge at the level of single organelles named autophagoproteasomes following mTOR inhibition Such a merging when considered at functional level might empower protein homeostasis and cell clearing [15,16]. With the aim to increase the therapeutic options for this incurable disease, we explored the ability of SG-2, already considered as a fully functional mimic of T1AM for behavioral and metabolic effects [13,20,21], to rescue β-amyloid neuronal dysfunction in mhAPP mice
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
