TABLE 1.
w
| Pathology | Background | Sirt2 downregulation | Pathway | Downstream changes | References |
| Aβ | H4-SW cellsAPP23 mice3xTG-AD micesAD cellsC57-BL6 mice | AGK2AK-7AK-7 AK-1SIRT2 KO/AK-1 | NA NA NA NA NA | ↓Aβ40 and Aβ42 ↑α secretase, ↓β secretase, ↓Aβ production ↓microtubule acetylation, ↓ALP impairment ↑microtubule stabilization, ↑autophagy, ↑cell survival, ↓toxic Aβ oligomers | Biella et al., 2016; Silva et al., 2017 |
| Tau | 3xTg-AD mice P301 cells 3xTg-AD mice rTg4510 mice | AK-7 AK-1 Nicotinamide AK-1 | NA NA ↑p25 NA | ↑steady-state level of tau, ↑microtubule stabilization ↑Ac-α-tubulin ↓Phospho-tau ↓Thr231-phosphotau, ↓monoubiquitinated tau, ↑tau degradation No effects on NFTs formation or stability | Biella et al., 2016;Esteves et al., 2019;Green et al., 2008;Spires-Jones et al., 2012 |
| α-synuclein | Human neuroglioma cells (H4) Drosophila PD modelH4 cellsMPTP model SH-SY5Y cells | SiRNA AGK-2 AK-1AGK-7 AK-1/AGK-2 shRNASIRT2 KOAGK-2 | NA NA NA NA NA NA NA FOXO3a pathway | ↓α-syn toxicity↓α-syn toxicity, ↑ larger inclusions formation↓α-syn toxicity, ↑ larger inclusions formation (less potent) No effects dose-dependent rescue of dorsomedial neurons↓SynT-positive inclusions, ↑ acetylated aSyn, ↑ALP (autophagy lysosome pathway) activity, ↑clearance of α-syn aggregates ↑TH positive neurons ↑ rotenone/diquat induced oxidative stress, ↑oxidative stress induced α-syn aggregation | Outeiro et al., 2007;de Oliveira et al., 2017; Singh et al., 2017 |
| Neuro- inflammation | BMDM cells RAW cells Primary rat astrocytes microglial BV2 cellsC57BL/6 mice (brain injury model) C57BL/6 mice (CCI injury model)N27 cells Treg cells from ipsilateral hemispheres of MCAO model senescence-accelerated mouse prone-8 (SAMP8) model | SIRT2 KO siRNA/control RNA/AGK-2/AK-1 AGK-2 SIRT2 siRNA AGK-2 AK-7 AGK-2 AGK-2 33i | NFκB pathwayNA NA NFκB pathwayNFκB pathway NA NANA | ↓LPS-induced inflammatory reactions↓Aβ-induced inflammation ↓LPS-induced inflammatory reactions ↓LPS-induced inflammatory reactions, ↓LPS-induced apoptosis ↑AQP-4 expression, cerebral edema and BBB disruption, ↑CCI injury model induced inflammation ↑histone acetylation, ↓LPS-induced inflammatory reactions ↑immunoregulatory activity of infiltrating Treg cells ↑glutamate receptor subunits GluN2A, GluN2B, and GluA1, ↓inflammation-related factors expression | Lee et al., 2014,Scuderi et al., 2014,Chen et al., 2015,Wang et al., 2016,Yuan et al., 2016,Harrison et al., 2018,Shu et al., 2019 Diaz-Perdigon et al., 2020 |
| Oxidative stress | MPTP model SH-SY5Y cells C57BL/6J cells | AK-7 AGK-2 SIRT2 KO | NA FOXO3a pathway NA | ↑GSH, ↓MDA, ↓oxidative stress ↑ rotenone/diquat induced oxidative stress↓endogenous antioxidant defense (Sod1, Sod2, Gpx1, and Cat), ↑oxidative stress | Guan et al., 2016,Singh et al., 2017,Fourcade et al., 2017 |
| Synaptic changes | DIV11 cultured hippocampal neurons cultured cortical neurons Sprague-Dawley rat | B2 siRNAB2 SIRT2 KO | NANA NA NA | ↑AMPARs expression↓internalization, ↑ AMPARs mediated synaptic transmission ↑ AMPARs acetylation, ↓AMPARs ubiquitination ↓LTP and LTD, ↓synaptic plasticity, ↓learning and memory | Wang et al., 2017 |
| Axonal degeneration | Wallerian degeneration slow (Wlds) mice cerebellar granule cells from Wlds mice C57BL/6J mice | Nicotinamide Nicotinamide/SIRT2 siRNA SIRT2 KO | NA NA NA | ↓axonal degeneration, ↑microtubule acetylation, ↑resistance to axonal degeneration ↓tubulin deacetylation, ↑resistance to axonal degeneration but not cell body ↑axonal degeneration | Wang et al., 2005,Suzuki and Koike, 2007,Fourcade et al., 2017 |
| Autophagy & Apoptosis | BV2 cells C57BL/6 mice SH-SY5Y cells C57BL/6 mice (brain injury model) H4 cells sAD cells C57-BL6 mice primary cortical neurons underlying OGD C57BL/6NTac mice with MCAO surgery sPD cells | AGK-2 SIRT2 KO SIRT2 shRNA AGK-2 shRNA AK-1 SIRT2 KO/AK1 AK-1 AGK-2 AGK-2 AK-1 | PARP activation NA Foxo3a pathway NFκB pathway NA NA NA FOXO3a/MAPK pathway FOXO3a/MAPK pathway NA | ↓ATP, ↑cell death ↓apoptosis ↓MPP-induced apoptosis ↓LPS-induced apoptosis ↑ALP activity ↓ALP impairment ↑autophagy, ↑cell survival, ↓toxic Aβ oligomers ↓apoptotic cell death ↓infarct size, ↑neurological outcome, ↓apoptotic factors ↑Ac-α-tubulin, ↑stability of microtubes, ↑normal autophagic flux | Li et al., 2013,Liu et al., 2014,Wang et al., 2016 de Oliveira et al., 2017,Silva et al., 2017 She et al., 2018,Esteves et al., 2018 |