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


Change log
Authors
Runfola, Massimiliano  ORCID logo  https://orcid.org/0000-0002-3608-2031
Yang, Xiaoting 
Bacci, Andrea 
Abstract

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.

Description
Keywords
Alzheimer’s disease, polypharmacology, C. elegans, autophagy, drug discovery, zebrafish, 5XFAD mice
Journal Title
Pharmaceuticals (Basel)
Conference Name
Journal ISSN
1424-8247
1424-8247
Volume Title
14
Publisher
MDPI AG
Sponsorship
Regione toscana (DEM-AGING)
Telethon Grant Projects (GGP20011)
MIUR (Dipartimenti di eccellenza 2018-2022)