Early sirtuin 2 inhibition prevents age-related cognitive decline in a senescence-accelerated mouse model

Abstract

The senescence-accelerated mouse prone-8 (SAMP8) model has been considered as a good model for aged-related cognitive decline and Alzheimer's disease (AD). Since epigenetic alterations represent a crucial mechanism during aging, in the present study we tested whether the inhibition of the histone deacetylase sirtuin 2 (SIRT2) could ameliorate the age-dependent cognitive impairments and associated neuropathology shown by SAMP8 mice. To this end, the potent SIRT2-selective inhibitor, 33i (5 mg/kg i. p. 8 weeks) was administered to 5-month-old (early treatment) and 8-month-old (late treatment) SAMP8 and aged matched control, senescence-accelerated mouse resistant-1 (SAMR1) mice. 33i administration to 5-month-old SAMP8 mice improved spatial learning and memory impairments shown by this strain in the Morris water maze. SAMP8 showed hyperphosphorylation of tau protein and decrease levels of SIRT1 in the hippocampus, which were not altered by 33i treatment. However, this treatment upregulated the glutamate receptor subunits GluN2A, GluN2B, and GluA1 in both SAMR1 and SAMP8. Moreover, early SIRT2 inhibition prevented neuroinflammation evidenced by reduced levels of GFAP, IL-1β, Il-6, and Tnf-α, providing a plausible explanation for the improvement of cognitive deficits shown by 33i-treated SAMP8 mice. When 33i was administered to 8-month-old SAMP8 with a severe established pathology, increases in GluN2A, GluN2B, and GluA1 were observed; however, it was not able to reverse the cognitive decline or the neuroinflammation. These results suggest that early SIRT2 inhibition might be beneficial in preventing agerelated cognitive deficits, neuroinflammation, and AD progression and could be an emerging candidate for the treatment of other diseases linked to dementia.

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).…”

“…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.…”

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

“…The senescence‐accelerated mouse prone 8 (SAMP8) strain is a spontaneous animal model of accelerated aging developed by selective inbreeding of the AKR/J strain. As it spontaneously shows AD‐like cognitive and behavioral alterations including cognitive impairment, Aβ deposition, and tau hyperphosphorylation, it has been widely used as AD model to explore the etiopathogenesis of sporadic AD (Diaz‐Perdigon et al, ).…”

HGF Mediates Clinical‐Grade Human Umbilical Cord‐Derived Mesenchymal Stem Cells Improved Functional Recovery in a Senescence‐Accelerated Mouse Model of Alzheimer's Disease

“…SAMP8 brains over‐produce APP, have increased tau phosphorylation, accompanied with gliosis and neuroinflammation. [ 20–22 ] Indeed, previous studies have reported on tau phosphorylation dynamics in SAMP8 mice, and various forms of hyperphosphorylated tau are more highly expressed in SAMP8 mice than in SAMR1 mice. [ 23–25 ] We visualized the NFT‐like pathology in hippocampal neurons in SAMP8 mouse brains by thioflavin‐S staining and found that PBS‐treated mice had more NFTs in the DG region than that in SAMR1 mice.…”