Identification of a Thyroid Hormone Derivative as a Pleiotropic Agent for the Treatment of Alzheimer’s Disease

Massimiliano Runfola, Michele Perni, Xiaoting Yang, Maria Marchese, Andrea Bacci, Serena Mero, Filippo M. Santorelli, Beatrice Polini, Grazia Chiellini, Daniela Giuliani, Antonietta Vilella, Martina Bodria, Eleonora Daini, Eleonora Vandini, Simon Rudge, Sheraz Gul, Michale O.J. Wakelam, Michele Vendruscolo, Simona Rapposelli

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number1330
Issue number12
Publication statusPublished - Dec 2021


  • 5XFAD mice
  • Alzheimer’s disease
  • Autophagy
  • C. elegans
  • Drug discovery
  • Polypharmacology
  • Zebrafish

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery


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