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.
Highlights
This article is an open access articleAlzheimer’s disease (AD) affects over 45 million people worldwide, a figure predicted to double by 2030 [1]
We evaluated the potential of SG2 as a polypharmacological strategy for AD drug discovery by assessing: (i) its capability to extend the lifespan and promote autophagy in an in vivo model of AD of C. elegans, (ii) its safety on small vertebrate model, zebrafish (Danio rerio), and (iii) its protective effects during the prodromal phase of AD
We employed a C. elegans model of AD in which human Aβ42 is constitutively expressed in the big muscle cells, leading to an age- and temperature-dependent paralysis [24]
Summary
Alzheimer’s disease (AD) affects over 45 million people worldwide, a figure predicted to double by 2030 [1]. This condition is characterized by the deposition in brain tissues of amyloid plaques formed by the amyloid β peptide (Aβ) and of neurofibrillary tangles formed by tau protein. Pharmaceuticals 2021, 14, 1330 symptoms [1]. Growing evidence suggests that the pathogenesis of AD is characterized by a tangled network of impaired mechanisms, including protein homeostasis disruption, neuro-inflammation, and lipid metabolism changes [2,3,4,5,6,7]. It is well established that defective autophagy is implicated in AD pathogenesis [8] and intracellular
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