Advancing age is the biggest risk factor for development for the major life-threatening diseases in industrialized nations accounting for >90% of deaths. Alzheimer's dementia (AD) is among the most devastating. Currently approved therapies fail to slow progression of the disease, providing only modest improvements in memory. Recently reported work describes mechanistic studies of J147, a promising therapeutic molecule previously shown to rescue the severe cognitive deficits exhibited by aged, transgenic AD mice. Apparently, J147 targets the mitochondrial alpha-F1-ATP synthase (ATP5A). Modest inhibition of the ATP synthase modulates intracellular calcium to activate AMP-activated protein kinase to inhibit mammalian target of rapamycin, a known mechanism of lifespan extension from worms to mammals.
Get full access to this article
View all access options for this article.
References
1.
BakerM. Deceptive curcumin offers cautionary tale for chemists. Nature, 2017; 541:144–145.
2.
NelsonKM, DahlinJL, BissonJ, GrahamJ, PauliGF, WaltersMA. The essential medicinal chemistry of curcumin. J Med Chem, 2017; 60:1620–1637.
3.
BaellJ, WaltersMA. Chemistry: Chemical con artists foil drug discovery. Nature, 2014; 513:481–483.
4.
BissonJ, McAlpineJB, FriesenJB, ChenS-N, GrahamJ, PauliGF. Can invalid bioactives undermine natural product-based drug discovery?. J Med Chem, 2016; 59:1671–1690.
5.
Burgos-MorónE, Calderón-MontañoJM, SalvadorJ, RoblesA, López-LázaroM. The dark side of curcumin. Int J Cancer, 2010; 126:1771–1775.
6.
BaellJB. Feeling nature's PAINS: Natural products, natural product drugs, and pan assay interference compounds (PAINS). J Nat Prod, 2016; 79:616–628.
7.
LimGP, ChuT, YangF, BeechW, FrautschySA, ColeGM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci, 2001; 21:8370–8377.
8.
YangF, LimGP, BegumAN, UbedaOJ, SimmonsMR, AmbegaokarSS, et al.Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem, 2005; 280:5892–5901.
9.
LiuY, DarguschR, MaherP, SchubertD. A broadly neuroprotective derivative of curcumin. J Neurochem, 2008; 105:1336–1345.
10.
SchubertDR, LiuY. Methods for protecting cells from amyloid toxicity and for inhibiting amyloid protein production. 2000. US Patent 6472436.
11.
ChenQ, PriorM, DarguschR, RobertsA, RiekR, EichmannC, et al.A novel neurotrophic drug for cognitive enhancement and Alzheimer's disease. PLoS One, 2011; 6:e27865.
12.
SavonenkoA, XuGM, MelnikovaT, MortonJL, GonzalesV, WongMPF, et al.Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer's disease: Relationships to beta-amyloid deposition and neurotransmitter abnormalities. Neurobiol Dis, 2005; 18:602–617.
13.
PriorM, DarguschR, EhrenJL, ChirutaC, SchubertD. The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer's disease mice. Alzheimers Res Ther, 2013; 5:25.
14.
GoldbergJ, CurraisA, PriorM, FischerW, ChirutaC, RatliffE, et al.The mitochondrial ATP synthase is a shared drug target for aging and dementia. Aging Cell, 2018 [Epub ahead of print]; DOI: 10.1111/acel.12715.
15.
PaiMY, LomenickB, HwangH, SchiestlR, McBrideW, LooJA, et al.Drug affinity responsive target stability (DARTS) for small molecule target identification. Methods Mol Biol, 2015; 1263:287–298.
16.
BainesCP. The molecular composition of the mitochondrial permeability transition pore. J Mol Cell Cardiol, 2009; 46:850–857.
17.
BernardiP, RasolaA, ForteM, LippeG. The mitochondrial permeability transition pore: Channel formation by F-ATP synthase, integration in signal transduction, and role in pathophysiology. Physiol Rev, 2015; 95:1111–1155.
18.
RaoVK, CarlsonEA, YanSS. Mitochondrial permeability transition pore is a potential drug target for neurodegeneration. Biochim Biophys Acta, 2014; 1842:1267–1272.
19.
ReddyPH, TripathiR, TroungQ, TirumalaK, ReddyTP, AnekondaV, et al.Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer's disease: Implications to mitochondria-targeted antioxidant therapeutics. Biochim Biophys Acta BBA - Mol Basis Dis, 2012; 1822:639–649.
20.
ZhangC, RissmanRA, FengJ. Characterization of ATP Alternations in an Alzheimer's Transgenic Mouse Model. J Alzheimers Dis JAD, 2015; 44:375–378.
21.
PerrySW, NormanJP, BarbieriJ, BrownEB, GelbardHA. Mitochondrial membrane potential probes and the proton gradient: A practical usage guide. Biotechniques, 2011; 50:98–115.
22.
FormentiniL, Sánchez-AragóM, Sánchez-CenizoL, CuezvaJM. The mitochondrial ATPase inhibitory factor 1 triggers a ROS-mediated retrograde prosurvival and proliferative response. Mol Cell, 2012; 45:731–742.
23.
SurinAM, KhirougS, GorbachevaLR, KhodorovBI, PinelisVG, KhirougL. Comparative analysis of cytosolic and mitochondrial ATP synthesis in embryonic and postnatal hippocampal neuronal cultures. Front Mol Neurosci, 2013; 5:102.
24.
PfeifferA, JaeckelM, LewerenzJ, NoackR, PouyaA, SchachtT, et al.Mitochondrial function and energy metabolism in neuronal HT22 cells resistant to oxidative stress. Br J Pharmacol, 2014; 171:2147–2158.
25.
RacioppiL, MeansAR. Calcium/calmodulin-dependent protein kinase kinase 2: Roles in signaling and pathophysiology. J Biol Chem, 2012; 287:31658–31665.
26.
BrookesPS, YoonY, RobothamJL, AndersMW, SheuS-S. Calcium, ATP, and ROS: A mitochondrial love-hate triangle. Am J Physiol Cell Physiol, 2004; 287:C817–C833.
27.
KimD-H, SarbassovDD, AliSM, KingJE, LatekRR, Erdjument-BromageH, et al.mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell, 2002; 110:163–175.
28.
FormentiniL, PereiraMP, Sánchez‐CenizoL, SantacatterinaF, LucasJJ, NavarroC, et al.In vivo inhibition of the mitochondrial H+‐ATP synthase in neurons promotes metabolic preconditioning. EMBO J, 2014; 33:762–778.
29.
TsangWY, SaylesLC, GradLI, PilgrimDB, LemireBD. Mitochondrial respiratory chain deficiency in Caenorhabditis elegans results in developmental arrest and increased life span. J Biol Chem, 2001; 276:32240–32246.
30.
DillinA, HsuA-L, Arantes-OliveiraN, Lehrer-GraiwerJ, HsinH, FraserAG, et al.Rates of behavior and aging specified by mitochondrial function during development. Science, 2002; 298:2398–2401.
31.
LeeSS, LeeRYN, FraserAG, KamathRS, AhringerJ, RuvkunG. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet, 2003; 33:40–48.
32.
CurranSP, RuvkunG. Lifespan regulation by evolutionarily conserved genes essential for viability. PLoS Genet, 2007; 3:e56.
33.
ChinRM, FuX, PaiMY, VergnesL, HwangH, DengG, et al.The metabolite alpha-ketoglutarate extends lifespan by inhibiting the ATP synthase and TOR. Nature, 2014; 510:397–401.
34.
SunX, WheelerCT, YolitzJ, LasloM, AlbericoT, SunY, et al.A mitochondrial ATP synthase subunit interacts with TOR signaling to modulate protein homeostasis and lifespan in Drosophila. Cell Rep, 2014; 8:1781–1792.
35.
ButterfieldDA, PoonHF. The senescence-accelerated prone mouse (SAMP8): A model of age-related cognitive decline with relevance to alterations of the gene expression and protein abnormalities in Alzheimer's disease. Exp Gerontol, 2005; 40:774–783.
36.
RangarajuS, SolisGM, ThompsonRC, Gomez-AmaroRL, KurianL, EncaladaSE, et al.Suppression of transcriptional drift extends C. elegans lifespan by postponing the onset of mortality. ELife, 2015; 4:e08833.
37.
López-OtínC, BlascoMA, PartridgeL, SerranoM, KroemerG. The hallmarks of aging. Cell, 2013; 153:1194–1217.
38.
CurraisA. Ageing and inflammation—A central role for mitochondria in brain health and disease. Ageing Res Rev, 2015; 21:30–42.
39.
ColmanRJ, AndersonRM, JohnsonSC, KastmanEK, KosmatkaKJ, BeasleyTM, et al.Caloric restriction delays disease onset and mortality in rhesus monkeys. Science, 2009; 325:201–204.
40.
MattisonJ, van der WeydenL, HubbardT, AdamsDJ. Cancer gene discovery in mouse and man. Biochim Biophys Acta, 2009; 1796:140–161.
41.
MattisonJA, ColmanRJ, BeasleyTM, AllisonDB, KemnitzJW, RothGS, et al.Caloric restriction improves health and survival of rhesus monkeys. Nat Commun, 2017; 8:14063.
42.
KenyonCJ. The genetics of ageing. Nature, 2010; 464:504–512.
43.
HarrisonDE, StrongR, SharpZD, NelsonJF, AstleCM, FlurkeyK, et al.Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 2009; 460:392–395.
44.
WilliamsDS, CashA, HamadaniL, DiemerT. Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway. Aging Cell, 2009; 8:765–768.
45.
LucanicM, HeldJM, VantipalliMC, KlangIM, GrahamJB, GibsonBW, et al.N-acylethanolamine signaling mediates the effect of diet on lifespan in C. elegans. Nature, 2011; 473:226–229.
46.
JohnsonSC, RabinovitchPS, KaeberleinM. mTOR is a key modulator of ageing and age-related disease. Nature, 2013; 493:338–345.
47.
ShabalinaIG, VyssokikhMY, GibanovaN, CsikaszRI, EdgarD, Hallden-WaldemarsonA, et al.Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1. Aging, 2017; 9:315–336.
ChenH-Y, XuD-P, TanG-L, CaiW, ZhangG-X, CuiW, et al.A potent multi-functional neuroprotective derivative of tetramethylpyrazine. J Mol Neurosci, 2015; 56:977–987.
50.
DaughertyDJ, MarquezA, CalcuttNA, SchubertD. A novel curcumin derivative for the treatment of diabetic neuropathy. Neuropharmacology, 2018; 129:26–35.
51.
ShenL-R, XiaoF, YuanP, ChenY, GaoQ-K, ParnellLD, et al.Curcumin-supplemented diets increase superoxide dismutase activity and mean lifespan in Drosophila. Age, 2013; 35:1133–1142.
52.
LeeK-S, LeeB-S, SemnaniS, AvanesianA, UmC-Y, JeonH-J, et al.Curcumin extends life span, improves health span, and modulates the expression of age-associated aging genes in Drosophila melanogaster. Rejuvenation Res, 2010; 13:561–570.
53.
SohJ-W, MarowskyN, NicholsTJ, RahmanAM, MiahT, SaraoP, et al.Curcumin is an early-acting stage-specific inducer of extended functional longevity in Drosophila. Exp Gerontol, 2013; 48:229–239.
