SUN-717 SG-2 a Novel Multi-Target Directed Ligand (MTDL) for the Treatment of Neurodegenerative Diseases (NDDS)

Abstract NDDs are progressive multifactorial disorders that impair memory, cognition, movements, and general functioning. This deterioration is mostly due to inflammation triggered by aberrant protein deposition, oxidative stress and modification in lipid pathways. Because of these multifactorial aspects, the development of multi-target directed ligand (MTDL) could represent a potential strategy for the treatment of NDDs. Recently, the thyronamine-like analog SG-2, originally developed as a synthetic TAAR1 agonist, has revealed to efficiently reprogram lipid metabolism and to produce memory-enhancement in mice1. Long-term potentiation (LTP) is one of the basic mechanisms of memory. LTP is inhibited by beta-Amyloid oligomers (Aβ), and in the early stage of AD it is selectively impaired in the entorhinal cortex (EC). In the present study, to further expand our knowledge on the potential of this novel analog to act as a neuroprotective agent, we investigated if administration of SG-2 has any effect on LTP in EC of a transgenic model of AD (hAPP-J20 mouse). Extracellular in vitro recordings were performed in EC slices from 2 month-old APP-J20 mice: field potentials were evoked in layer II after stimulation of the same layer and LTP was elicited by high frequency stimulation (HFS), consisting of three trains of 100 pulses at 100Hz. SG-2 (1 or 5μM) was administered for 10 minutes, starting 5 minutes before the delivery of HFS. LTP cannot be elicited by HFS in mhAPP slices perfused with artificial cerebrospinal fluid (ACSF) alone. When we tried to rescue LTP in mhAPP slices using SG2 at the lowest concentration (1µM), 10 min perfusion with SG2 was not effective. In contrast, a higher concentration of SG2 (5 μM), rescued LTP to a level that was significantly higher than that observed in mhAPP slices alone (n=6; p=0.046), as well as in mhAPP slices perfused with SG2 1 μM (n=5; p=0.043). Our results suggest that SG-2 plays a neuroprotective effect, rescuing Aβ-induced neuronal dysfunction and might open new perspective in the study of AD. Metabolic reprogramming and neuroprotective functions for the histone deacetylase SIRT6 are well known, and a reduction of SIRT6 expression has been observed in patients with AD. Exposure of human neuroblastoma (SH-SY5Y) cells to SG-2 (1 or 10 μM) resulted in significant (p=0.044) over-expression of SIRT6, and concomitant activation of AMPK leading to the inhibition of mTOR phosphorylation, further underlying potential for SG-2 as a multi-target neuroprotective ligand.