The identification of effective pharmacological tools for Alzheimer’s disease (AD) represents one of the main challenges for therapeutic discovery. Due to the variety of pathological processes associated with AD, a promising route for pharmacological intervention involves the development of new chemical entities that can restore cellular homeostasis. To investigate this strategy, we designed and synthetized SG2, a compound related to the thyroid hormone thyroxine, that shares a pleiotropic activity with its endogenous parent compound, including autophagic flux promotion, neuroprotection, and metabolic reprogramming. We demonstrate herein that SG2 acts in a pleiotropic manner to induce recovery in a C. elegans model of AD based on the overexpression of Aβ42 and improves learning abilities in the 5XFAD mouse model of AD. Further, in vitro ADME-Tox profiling and toxicological studies in zebrafish confirmed the low toxicity of this compound, which represents a chemical starting point for AD drug development.

Identification of a Thyroid Hormone Derivative as a Pleiotropic Agent for the Treatment of Alzheimer’s Disease / Runfola, M.; Perni, M.; Yang, X.; Marchese, M.; Bacci, A.; Mero, S.; Santorelli, F. M.; Polini, B.; Chiellini, G.; Giuliani, D.; Vilella, A.; Bodria, M.; Daini, E.; Vandini, E.; Rudge, S.; Gul, S.; Wakelam, M. O. J.; Vendruscolo, M.; Rapposelli, S.. - In: PHARMACEUTICALS. - ISSN 1424-8247. - 14:12(2021), pp. 1330-1337. [10.3390/ph14121330]

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