Sirtuin 2 Inhibition Improves Cognitive Performance and Acts on Amyloid-β Protein Precursor Processing in Two Alzheimer’s Disease Mouse Models

Abstract

The neuropathological hallmarks of Alzheimer's disease (AD) are extracellular plaques built up by the accumulation of the amyloid-β protein precursor (AβPP)-derived peptide β (Aβ), and intracellular tangles of hyperphosphorylated tau protein. Sirtuin 2 (SIRT2) is a member of the sirtuin family, featuring conserved enzymes with deacetylase activity and involved in several cell molecular pathways. We investigated the importance of SIRT2 inhibition in AD. We inhibited SIRT2 by small molecules (AGK-2, AK-7) and examined AβPP metabolism in H4-SW neuroglioma cells overexpressing AβPP and two AD transgenic mouse models (3xTg-AD and APP23). The in vitro studies suggested that the inhibition of SIRT2 reduced Aβ production; in vivo data showed an improvement of cognitive performance in the novel object recognition test, and an effect on AβPP proteolytic processing leading to a reduction of soluble β-AβPP and an increase of soluble α-AβPP protein. In 3xTg-AD mice, we noticed that total tau protein level rose. Overall, our pre-clinical data support a role for SIRT2 inhibition in the improvement of cognitive performance and the modulation of molecular mechanisms relevant for AD, thus deserving attention as possible therapeutic strategy.

RTN4B‐mediated suppression of Sirtuin 2 activity ameliorates β‐amyloid pathology and cognitive impairment in Alzheimer's disease mouse model

“…Although AD is a neurodegenerative disease, non‐invasive treatment with blood‐brain barrier permeable drugs is still the optimal choice. Our results were consistent with previous reports that AK‐7 administration can improve cognition in two other AD mice models (Biella et al, 2016) and that another SIRT2 inhibitor can improve cognition in a senescence‐accelerated mouse model (Diaz‐Perdigon et al, 2020). Furthermore, we confirmed that SIRT2 inhibition reduces the Aβ burden, mainly by curtailing APP processing, via the regulation of BACE1 in vivo, which was also supported by another study that showed SIRT2 inhibition decreased Aβ levels in vitro (Biella et al, 2016).…”

“…Our results were consistent with previous reports that AK‐7 administration can improve cognition in two other AD mice models (Biella et al, 2016) and that another SIRT2 inhibitor can improve cognition in a senescence‐accelerated mouse model (Diaz‐Perdigon et al, 2020). Furthermore, we confirmed that SIRT2 inhibition reduces the Aβ burden, mainly by curtailing APP processing, via the regulation of BACE1 in vivo, which was also supported by another study that showed SIRT2 inhibition decreased Aβ levels in vitro (Biella et al, 2016). Considering SIRT2 and SIRT1 have been reported showed an opposite effect on neurodegeneration (Donmez & Outeiro, 2013), for eliminating the possible feedback increase of SIRT1 caused by SIRT2 inhibition, we also assayed the expression level of SIRT1 in the context of SIRT2 pharmacological or genetic inhibition.…”

“…Furthermore, SIRT2 mRNA levels increased in the peripheral blood of patients with AD (Wongchitrat et al, 2019), and SIRT2 levels escalated alongside the decreased acetylation of its recognized substrate α‐tubulin in the AD brain (Silva, Esteves, Oliveira, & Cardoso, 2016). Moreover, recent studies showed that the interference of SIRT2 mitigated AD‐like recognition deficits in both the mouse model of neurodegenerative diseases and the aged‐accelerated mouse model (Biella et al, 2016; Diaz‐Perdigon et al, 2020). These above pieces of evidence suggested that SIRT2 might play a significant role in CNS and represent a potential drug target for AD.…”

Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders

“…It interacts with the transcription factor NF-κB, with PARP and with other proteins engaged in DNA repair; this suggests SIRT6 as another promising target in the regulation of longevity [73, 105]. Till now controversial findings are published on the role of SIRT2 which might be important for longevity but also seems to take part in Aβ production, α-synuclein toxicity, and neuronal cell death [74, 145, 188]. Insufficient data are available on SIRT4 and SIRT5 in mitochondria; the knowledge on sirtuin interactions in the regulation of cell survival and death in physiology and pathology is also leaving something to be desired.…”

“…SIRT1 might also protect against synapse loss, a more subtle and earlier effect of Aβ pathology [139]. In turn, small-molecule SIRT2 inhibitors 3-(1-azepanylsulfonyl)- N -(3-bromphenyl) benzamide (AK-7) and 2-cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]- N -5-quinolinyl-2-propenamide (AGK2) have shifted the balance between α- and β-secretase reducing the Aβ load and led to cognitive improvement in two transgenic mouse models [145]. AGK-2 also reduced glial activation by Aβ 1-42 [144].…”