The compound 33i, a new SIRT2 inhibitor, as a potential treatment for Alzheimer’s disease

Abstract

Alzheimer s disease (AD) is the most common form of dementia and one of the leading causes of morbidity and mortality in the aging population. Although its exact etiology remains to be elucidated, it is likely to result from complex interactions between genetic, epigenetic, and environmental factors, with age as the main risk factor. Therefore, understanding the changes and alterations that occur during aging is essential to understand the aetiology of AD and to establish new pharmacological therapies. In this line, several studies have identified a major role for the histone deacetylase SIRT2 in aging and different neurodegenerative diseases, including AD. Among all sirtuins, SIRT2 expression is found strongest in the brain. Although its biological functions are not well described yet, mounting evidence indicates that excess of SIRT2 might be deleterious to neurons; hence its inhibition is postulated as a novel promising therapeutic strategy to tackle a wide variety of hallmarks that are altered during aging and neurodegenerative diseases. Based on the observations previously mentioned, the overarching objective of this study is to investigate SIRT2 inhibition as a future potential treatment for AD. For this, a preliminary in vitro toxicological evaluation was performed, followed by an extensive pharmacological study of the compound 33i, a new potent SIRT2-selective inhibitor. More precisely, the specific aim of this study is to propose the 33i molecule as a pharmacological strategy to prevent, improve or even reverse the functional and molecular alterations in two different mouse models of AD representing the sporadic and familial forms of the disease. Results show that 33i treatment was effective, through the modulation of glutamate receptors and neuroinflammation, when SIRT2 was inhibited in animals that presented an early pathology. From this perspective, this pharmacological strategy could be an ideal novel target to prevent age-related cognitive decline and neurodegeneration. In summary, given its efficacy and safety, the 33i compound seams a good pharmacological strategy to treat AD. Altogether, 33i has proved to be effective since it improves the cognitive deficit in two different AD mouse models, increases different glutamate subunit receptors, prevents the neuroinflammation when administered at early stages of the disease in the SAMP8 model and reduces the amyloid pathology in the APP/PS1 model. In addition, the lack of mutagenicity or genotoxicity observed in vitro after 33i treatment makes this molecule a promising safe epigenetic pharmacological drug.