Unravelling the role of SIRT2 in Alzheimer’s disease

Abstract

Sirtuin 2 (SIRT2) has been proposed to have a central role on ageing, inflammation, and age-related pathologies such as AD. Recent studies propose the pharmacological inhibition of SIRT2 as a therapeutic strategy for several neurodegenerative diseases; nevertheless, its specific role is not well understood which varies depending on the organs, cell types and contexts analyzed. In attempt to understand the role of SIRT2 in ageing, the specific isoform 3 of SIRT2 (SIRT2.3) was overexpressed in mice hippocampus. Although, SIRT2.3 overexpression was not enough to accelerate ageing in a model with normal pattern of ageing, it promoted neuroinflammation and worsened age-related cognitive decline in the SAMP8 strain with an accelerated ageing phenotype. In this context, we postulated that its pharmacological inhibition could be a pharmacological strategy for the treatment of AD. Indeed, SIRT2 inhibition improved learning and memory deficits and reduced amyloid pathology and neuroinflammation; however, it increased peripheral inflammation. These peripheral deleterious effects were confirmed when the blood-brain barrier-impermeable SIRT2 inhibitor AGK-2 was administered. In this scenario where a beneficial effect of central SIRT2 inhibition while a deleterious peripheral effect was observed, we hypothesized that the specific deletion of SIRT2 in microglial cells could be the best therapeutic strategy to minimize the possible adverse effects. Upon an acute inflammatory insult, microglial SIRT2 deficiency reduced the inflammatory response. However, microglial SIRT2 seems to be essential in a chronic inflammatory context, such as AD, since its deletion increased mortality, worsened cognition, and impaired amyloid pathology in APP PS1 mouse model. These results highlight the relevance of further investigate the specific functions of SIRT2 in each cell type which is essential to maximize its potential as pharmacological target not only for AD but also for other neurodegenerative diseases.