Silent information-regulated transcription factor 1 (SIRT1) is the most prominent and widely studied member of the sirtuins (a family of mammalian class III histone deacetylases). It is a nuclear protein, and the deacetylation of the peroxisome proliferator-activated receptor coactivator-1 has been extensively implicated in metabolic control and mitochondrial biogenesis and is the basis for studies into its involvement in caloric restriction and its effects on lifespan. The present study discusses the potentially protective mechanism of SIRT1 in the regulation of the mitochondrial biogenesis and autophagy involved in the modulation of Alzheimer’s disease, which may be correlated with the role of SIRT1 in affecting neuronal morphology, learning, and memory during development; regulating metabolism; counteracting stress responses; and maintaining genomic stability. Drugs that activate SIRT1 may offer a promising approach to treating Alzheimer’s disease.
SongSB, JangSY, KangHT, WeiB, JeounUW, YoonGS, HwangES (2017) Modulation of mitochondrial membrane potential and ROS generation by nicotinamide in a manner independent of SIRT1 and mitophagy. Mol Cells40, 503–514.
2.
LiY, WangP, YangX, WangW, ZhangJ, HeY, ZhangW, JingT, WangB, LinR (2016) SIRT1 inhibits inflammatory response partly through regulation of NLRP3 inflammasome in vascular endothelial cells. Mol Immunol77, 148–156.
3.
SheDT, JoDG, ArumugamTV (2017) Emerging roles of sirtuins in ischemic stroke. Transl Stroke Res8, 405–423.
4.
SatohA, ImaiSI, GuarenteL (2017) The brain, sirtuins, and ageing. Nat Rev Neurosci18, 362–374.
5.
Della-MorteD, DaveKR, DeFazioRA, BaoYC, RavalAP, Perez-PinzonMA (2009) Resveratrol pretreatment protects rat brain from cerebral ischemic damage via a sirtuin 1-uncoupling protein 2 pathway. Neuroscience159, 993–1002.
ChoSH, ChenJA, SayedF, WardME, GaoF, NguyenTA, KrabbeG, SohnPD, LoI, MinamiS, DevidzeN, ZhouY, CoppolaG, GanL (2015) SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1β. J Neurosci35, 807–818.
8.
ChenC, ZhouM, GeY, WangX (2020) SIRT1 and aging related signaling pathways. Mech Ageing Dev187, 111215.
9.
YeungF, HobergJE, RamseyCS, KellerMD, JonesDR, FryeRA, MayoMW (2004) Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J23, 2369–2380.
10.
MinSW, SohnPD, LiY, DevidzeN, JohnsonJR, KroganNJ, MasliahE, MokSA, GestwickiJE, GanL (2018) SIRT1 deacetylates tau and reduces pathogenic tau spread in a mouse model of tauopathy. J Neurosci38, 3680–3688.
11.
MinSW, ChoSH, ZhouY, SchroederS, HaroutunianV, SeeleyWW, HuangEJ, ShenY, MasliahE, MukherjeeC, MeyersD, ColePA, OttM, GanL (2010) Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron67, 953–966.
12.
EveredL, SilbertB, KnopmanDS, ScottDA, DeKoskyST, RasmussenLS, OhES, CrosbyG, BergerM, EckenhoffRG; Nomenclature Consensus Working Group (2018) Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018. J Alzheimers Dis66, 1–10.
13.
GuarenteL (2013) Calorie restriction and sirtuins revisited. Genes Dev27, 2072–2085.
14.
GaoJ, WangWY, MaoYW, GräffJ, GuanJS, PanL, MakG, KimD, SuSC, TsaiLH (2010) A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature466, 1105–1109.
15.
MichánS, LiY, ChouMM, ParrellaE, GeH, LongJM, AllardJS, LewisK, MillerM, XuW, MervisRF, ChenJ, GuerinKI, SmithLE, McBurneyMW, SinclairDA, BaudryM, de CaboR, LongoVD (2010) SIRT1 is essential for normal cognitive function and synaptic plasticity. J Neurosci30, 9695–9707.
16.
ShahSA, YoonGH, ChungSS, AbidMN, KimTH, LeeHY, KimMO (2017) Novel osmotin inhibits SREBP2 via the AdipoR1/AMPK/SIRT1 pathway to improve Alzheimer’s disease neuropathological deficits. Mol Psychiatry22, 407–416.
17.
QinW, YangT, HoL, ZhaoZ, WangJ, ChenL, ZhaoW, ThiyagarajanM, MacGroganD, RodgersJT, PuigserverP, SadoshimaJ, DengH, PedriniS, GandyS, SauveAA, PasinettiGM (2006) Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem281, 21745–21754.
18.
OosterhofN, DekensDW, LawermanTF, van DijkM (2012) Yet another role for SIRT1: Reduction of α-synuclein aggregation in stressed neurons. J Neurosci32, 6413–6414.
19.
JeongH, CohenDE, CuiL, SupinskiA, SavasJN, MazzulliJR, YatesJR3rd, BordoneL, GuarenteL, KraincD (2011) Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med18, 159–165.
20.
JiangM, WangJ, FuJ, DuL, JeongH, WestT, XiangL, PengQ, HouZ, CaiH, SeredeninaT, ArbezN, ZhuS, SommersK, QianJ, ZhangJ, MoriS, YangXW, TamashiroKL, AjaS, MoranTH, Luthi-CarterR, MartinB, MaudsleyS, MattsonMP, CichewiczRH, RossCA, HoltzmanDM, KraincD, DuanW (2011) Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets. Nat Med18, 153–158.
21.
MontieHL, PestellRG, MerryDE (2011) SIRT1 modulates aggregation and toxicity through deacetylation of the androgen receptor in cell models of SBMA. J Neurosci31, 17425–17436.
22.
Fonseca-KellyZ, NassrallahM, UribeJ, KhanRS, DineK, DuttM, ShindlerKS (2012) Resveratrol neuroprotection in a chronic mouse model of multiple sclerosis. Front Neurol3, 84.
GuarenteL (2011) Franklin H. Epstein Lecture: Sirtuins, aging, and medicine. N Engl J Med364, 2235–2244.
25.
HerskovitsAZ, GuarenteL (2014) SIRT1 in neurodevelopment and brain senescence. Neuron81, 471–483.
26.
TheendakaraV, PatentA, Peters LibeuCA, PhilpotB, FloresS, DescampsO, PoksayKS, ZhangQ, CailingG, HartM, JohnV, RaoRV, BredesenDE (2013) Neuroprotective Sirtuin ratio reversed by ApoE4. Proc Natl Acad Sci U S A110, 18303–18308.
27.
ChenD, SteeleAD, LindquistS, GuarenteL (2005) Increase in activity during calorie restriction requires Sirt1. Science310, 1641.
28.
CodocedoJF, AllardC, GodoyJA, Varela-NallarL, InestrosaNC (2012) SIRT1 regulates dendritic development in hippocampal neurons. PLoS One7, e47073.
29.
SuginoT, MaruyamaM, TannoM, KunoA, HoukinK, HorioY (2010) Protein deacetylase SIRT1 in the cytoplasm promotes nerve growth factor-induced neurite outgrowth in PC12 cells. FEBS Lett584, 2821–2826.
30.
HisaharaS, ChibaS, MatsumotoH, TannoM, YagiH, ShimohamaS, SatoM, HorioY (2008) Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation. Proc Natl Acad Sci U S A105, 15599–15604.
31.
GuoW, QianL, ZhangJ, ZhangW, MorrisonA, HayesP, WilsonS, ChenT, ZhaoJ (2011) Sirt1 overexpression in neurons promotes neurite outgrowth and cell survival through inhibition of the mTOR signaling. J Neurosci Res89, 1723–1736.
32.
LiXH, ChenC, TuY, SunHT, ZhaoML, ChengSX, QuY, ZhangS (2013) Sirt1 promotes axonogenesis by deacetylation of Akt and inactivation of GSK3. Mol Neurobiol48, 490–499.
33.
LiuCM, WangRY, Saijilafu, JiaoZX, ZhangBY, ZhouFQ (2013) MicroRNA-138 and SIRT1 form a mutual negative feedback loop to regulate mammalian axon regeneration. Genes Dev27, 1473–1483.
34.
DietrichMO, AntunesC, GeliangG, LiuZW, BorokE, NieY, XuAW, SouzaDO, GaoQ, DianoS, GaoXB, HorvathTL (2010) Agrp neurons mediate Sirt1’s action on the melanocortin system and energy balance: Roles for Sirt1 in neuronal firing and synaptic plasticity. J Neurosci30, 11815–11825.
35.
ZhaoYN, LiWF, LiF, ZhangZ, DaiYD, XuAL, QiC, GaoJM, GaoJ (2013) Resveratrol improves learning and memory in normally aged mice through microRNA-CREB pathway. Biochem Biophys Res Commun435, 597–602.
36.
MichishitaE, ParkJY, BurneskisJM, BarrettJC, HorikawaI (2005) Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell16, 4623–4635.
37.
VaqueroA, ScherMB, LeeDH, SuttonA, ChengHL, AltFW, SerranoL, SternglanzR, ReinbergD (2006) SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. Genes Dev20, 1256–1261.
38.
VaqueroA, ScherM, Erdjument-BromageH, TempstP, SerranoL, ReinbergD (2007) SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation. Nature450, 440–444.
39.
KaarnirantaK, KajdanekJ, MorawiecJ, PawlowskaE, BlasiakJ (2018) PGC-1α protects RPE cells of the aging retina against oxidative stress-induced degeneration through the regulation of senescence and mitochondrial quality control. The significance for AMD pathogenesis. Int J Mol Sci19, 2317.
VegaRB, HortonJL, KellyDP (2015) Maintaining ancient organelles: Mitochondrial biogenesis and maturation. Circ Res116, 1820–1834.
42.
AustinS, St-PierreJ (2012) PGC1α and mitochondrial metabolism–emerging concepts and relevance in ageing and neurodegenerative disorders. J Cell Sci125, 4963–4971.
43.
NemotoS, FergussonMM, FinkelT (2005) SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1alpha. J Biol Chem280, 16456–16460.
44.
CampbellCT, KolesarJE, KaufmanBA (2012) Mitochondrial transcription factor A regulates mitochondrial transcription initiation, DNA packaging, and genome copy number. Biochim Biophys Acta1819, 921–929.
SuzukiM, BartlettJD (2014) Sirtuin1 and autophagy protect cells from fluoride-induced cell stress. Biochim Biophys Acta1842, 245–255.
53.
YanJ, LuoA, GaoJ, TangX, ZhaoY, ZhouB, ZhouZ, LiS (2019) The role of SIRT1 in neuroinflammation and cognitive dysfunction in aged rats after anesthesia and surgery. Am J Transl Res11, 1555–1568.
54.
KangHT, HwangES (2009) Nicotinamide enhances mitochondria quality through autophagy activation in human cells. Aging Cell8, 426–438.
55.
ChenL, ZhangJ, LiC, WangZ, LiJ, ZhaoD, WangS, ZhangH, HuangY, GuoX (2018) Glycine Transporter-1 and glycine receptor mediate the antioxidant effect of glycine in diabetic rat islets and INS-1 cells. Free Radic Biol Med123, 53–61.
56.
JangSY, KangHT, HwangES (2012) Nicotinamide-induced mitophagy: Event mediated by high NAD+/NADH ratio and SIRT1 protein activation. J Biol Chem287, 19304–19314.
57.
RakovicA, ZieglerJ, MårtenssonCU, PrasuhnJ, ShurkewitschK, KönigP, PaulsonHL, KleinC (2019) PINK1-dependent mitophagy is driven by the UPS and can occur independently of LC3 conversion. Cell Death Differ26, 1428–1441.
58.
ConteA, PellegriniS, TagliazucchiD (2003) Synergistic protection of PC12 cells from beta-amyloid toxicity by resveratrol and catechin. Brain Res Bull62, 29–38.
HanYS, ZhengWH, BastianettoS, ChabotJG, QuirionR (2004) Neuroprotective effects of resveratrol against beta-amyloid-induced neurotoxicity in rat hippocampal neurons: Involvement of protein kinase C. Br J Pharmacol141, 997–1005.
61.
KaruppagounderSS, PintoJT, XuH, ChenHL, BealMF, GibsonGE (2009) Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer’s disease. Neurochem Int54, 111–118.
FrozzaRL, LourencoMV, De FeliceFG (2018) Challenges for Alzheimer’s disease therapy: Insights from novel mechanisms beyond memory defects. Front Neurosci12, 37.
64.
HaraY, McKeehanN, FillitHM (2019) Translating the biology of aging into novel therapeutics for Alzheimer disease. Neurology92, 84–93.
65.
SluggettJK, KoponenM, BellJS, TaipaleH, TanskanenA, TiihonenJ, UusitupaM, TolppanenAM, HartikainenS (2020) Metformin and risk of Alzheimer’s disease among community-dwelling people with diabetes: A national case-control study. J Clin Endocrinol Metab105, dgz234.
66.
BiesselsGJ, VerhagenC, JanssenJ, van den BergE, ZinmanB, RosenstockJ, GeorgeJT, PasseraA, SchnaidtS, JohansenOE; CARMELINA Investigators (2019) Effect of linagliptin on cognitive performance in patients with type 2 diabetes and cardiorenal comorbidities: The CARMELINA Randomized Trial. Diabetes Care42, 1930–1938.
67.
DavisKAS, BisharaD, PereraG, MolokhiaM, RajendranL, StewartRJ (2020) Benefits and harms of statins in people with dementia: A systematic review and meta-analysis. J Am Geriatr Soc68, 650–658.
68.
KimD, NguyenMD, DobbinMM, FischerA, SananbenesiF, RodgersJT, DelalleI, BaurJA, SuiG, ArmourSM, PuigserverP, SinclairDA, TsaiLH (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J26, 3169–3179.
69.
CohenTJ, GuoJL, HurtadoDE, KwongLK, MillsIP, TrojanowskiJQ, LeeVM (2011) The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat Commun2, 252.
70.
Róna-VörösK, WeydtP (2010) The role of PGC-1α in the pathogenesis of neurodegenerative disorders. Curr Drug Targets11, 1262–1269.
71.
TsunemiT, La SpadaAR (2012) PGC-1α at the intersection of bioenergetics regulation and neuron function: From Huntington’s disease to Parkinson’s disease and beyond. Prog Neurobiol97, 142–151.
72.
MouchiroudL, HoutkooperRH, MoullanN, KatsyubaE, RyuD, CantóC, MottisA, JoYS, ViswanathanM, SchoonjansK, GuarenteL, AuwerxJ (2013) The NAD(+)/Sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell154, 430–441.
73.
RamseyKM, MillsKF, SatohA, ImaiS (2008) Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing (BESTO) mice. Aging Cell7, 78–88.
74.
BraidyN, PoljakA, GrantR, JayasenaT, MansourH, Chan-LingT, GuilleminGJ, SmytheG, SachdevP (2014) Mapping NAD(+) metabolism in the brain of ageing Wistar rats: Potential targets for influencing brain senescence. Biogerontology15, 177–198.
75.
MassudiH, GrantR, BraidyN, GuestJ, FarnsworthB, GuilleminGJ (2012) Age-associated changes in oxidative stress and NAD+metabolism in human tissue. PLoS One7, e42357.
