Oxidative stress, dysfunctional glucose metabo.pdf

Alzheimer disease(AD)is characterized by an accumula-tion of senile plaques(SPs;composed mostly of fibrillary amyloid-(A)peptide and dystrophic neurites)and neurofibrillary tangles(NFTs;composed of hyperphos-phorylated tau protein)in the brain,leading to dysfunc-tion and loss of synapses and eventual neuronal death1,2.Clinically,AD is characterized by several features,nota-bly a progressive cognitive decline involving loss of mem-ory and higher executive functioning1.Arguably,the earliest stage of AD is preclinical AD(PCAD),in which persons have normal cognitive status but upon death and autopsy their brains display evidence of substantial AD neuro-pathology.Amnestic mild cognitive impairment(aMCI)is a progressive condition in which there is some degree of memory loss and is widely thought to be a prodromal early stage of AD in which AD neuropathology is pres-ent,albeit to a lesser degree.In contrast to patients with AD,however,aMCI individuals can perform activities of daily living.It has been estimated that approximately 15%of people with aMCI progress to AD annually3.AD pathology occurs well before(up to two decades)the onset of clinical symptoms24.It follows that therapy that begins when symptoms appear may be too late to be effective,and understanding key molecular processes in the progression of AD is needed to facilitate earlier diagnosis and to develop new interventions to slow or stop its progression.One important process that becomes dysfunctional in AD and aMCI is the metabolism of glucose5,6.Glucose is normally the major energy source for the brain and is metabolized to ATP via glycolysis,the tricarboxylic acid(TCA)cycle and the electron transport chain(ETC),as shown in Fig.1.Glucose enters the brain from the vascu-lature through highly efficient glucose transporters and requires insulin for optimal cellular utilization7.In AD and aMCI,however,brain insulin resistance is present6,7.Indeed,type 2 diabetes(T2DM),a key component of which is insulin resistance,is a substantial risk factor for developing AD7.Given the very large increase in T2DM development worldwide,combined with ageing populations,AD is a major and growing problem.This Review summarizes the role of oxidative damage in aMCI and AD,how it affects glucose metabolism and how it is a key mechanism behind insulin resistance.We review the reasons for the failures of certain therapeutic approaches in AD and suggest possible new approaches.Oxidative damage is relevant to ADOxidative damage is the damage that is done to biomol-ecules during oxidative stress(for a detailed review and discussion,see reF.8).Oxidative stress is a serious imbal-ance between the production of reactive oxygen species(ROS)and reactive nitrogen species(RNS)and anti-oxidant defences8,and has been shown in a wide range of studies to contribute significantly to the pathogen-esis and progression of AD2,819.Diabetes also leads to oxidative stress(reF.8,also see later discussion),which may make a contribution to its propensity to favour AD development9.The term reactive is variable:some ROS and RNS are highly reactive(for example,OH)whereas other are much more selective in their reac-tions(for example,H2O2,NO,O2).Table1 lists several biologically important ROS and RNS.When certain ROS or RNS react with biomolecules,oxidative or nitrosative damage occurs,which can be detected by measuring specific products that result from such damage(biomarkers of oxidative or nitrosative damage)8.Some of the most commonly used biomarkers of oxidative damage to lipids,proteins and nucleic acids are listed in Table2.Higher executive functioningCognitive processes that include planning,reasoning and problem solving that in humans largely involve the prefrontal cortex,with connections to other brain areas.Reactive oxygen species(rOS).Oxygen-containing species that contain unpaired electrons(which makes them free radicals)or from which free radicals are easily derived.Reactive nitrogen species(rNS).Nitrogen-containing species that are free radicals or moieties from which free radicals are easily derived.Oxidative stress,dysfunctional glucose metabolism and Alzheimer diseaseD.AllanButterfield1 and BarryHalliwell2*Abstract|Alzheimer disease(AD)is a major cause of age-related dementia.We do not fully understand AD aetiology and pathogenesis,but oxidative damage is a key component.The brain mostly uses glucose for energy,but in AD and amnestic mild cognitive impairment glucose metabolism is dramatically decreased,probably owing,at least in part,to oxidative damage to enzymes involved in glycolysis,the tricarboxylic acid cycle and ATP biosynthesis.Consequently,ATP-requiring processes for cognitive function are impaired,and synaptic dysfunction and neuronal death result,with ensuing thinning of key brain areas.We summarize current research on the interplay and sequence of these processes and suggest potential pharmacological interventions to retard AD progression.1Department of Chemistry and Sanders-Brown Center on Aging,University of Kentucky,Lexington,KY,USA.2Department of Biochemistry and Centre for Ageing and Neurobiology,National University of Singapore,Singapore,Singapore.*e-mail:bchbhnus.edu.sghttps:/doi.org/10.1038/s41583-019-0132-6 Alzheimer DiseA 2019|voluMe 20 In the brains of individuals with PCAD and AD,lev-els of oxidative damage to a wide range of molecules are increased819.For example,levels of protein carbonyls(PCs)are elevated in AD in brain regions that are rich in A-peptide-containing SPs(Table2)but are at nor-mal levels in brain regions devoid of A-rich plaques19.Even in patients with aMCI,oxidative damage is already signi ficantly increased:PCs are significantly elevated in Outer membraneH+H+H+H+H+H+H+H+H+H+H+H+Intermembrane spaceMitochondrionGlycolysisGlucoseHexokinasePhosphoglucoisomerasePhosphoglycerate kinasePyruvate kinaseG6PF6PPhosphofructokinaseGlyceraldehyde-3-phosphate dehydrogenaseFBPDHAPG3P1,3-BPGFructose bisphosphate aldolasePyruvate dehydrogenaseMalate dehydrogenaseCitrate synthaseAconitaseIsocitrate dehydrogenaseSuccinyl-CoA synthetaseSuccinate dehydrogenase-KG dehydrogenaseEnolaseTriosephosphate isomerase3-PGPhosphoglycerate mutase2-PGPEPPyruvateAcetyl-CoATCA cycleCitrateIsocitrate-KGSuccinyl-CoASuccinateFumarateMalateOAAInner membraneATP synthaseProton gradientFumaraseMatrix NADH FADH2NAD+NADHFADH2FADDamaged in ADATP formationNADH formationFADH2 formationIIIIIIIVFig.1|Schematic diagrams of the biochemistry of glucose catabolism and ATP synthesis and their oxidative dysfunction in AD and aMCI brains.Glycolysis,the tricarboxylic acid(TCA)cycle and the electron transport chain(ETC),the latter localized on the inner mitochondrial membrane,work together to catabolize glucose and drive ATP synthesis via the ATP synthase complex.Complexes IIV of the ETC are shown.Also shown is ATP synthase,the-chain of which is oxidatively modified in brains of subjects with Alzheimer disease(AD).Briefly,this figure shows that glucose is converted to pyruvate in glycolysis.Pyruvate is converted to acetyl-CoA,which enters the TCA cycle,and the resulting reducing equivalents(NADH and FADH2)from glycolysis and the TCA cycle enter the mitochondrial ETC.The inner mitochondrial membrane is impermeable to NADH;therefore,the malateaspartate shuttle leads to NADH synthesis in the matrix via NADH in the cytosol to reduce oxygen to water,leading to production of a mitochondrial proton gradient in the intermembrane space that drives ATP synthesis.Reactions catalysed by specific enzymes or enzyme complexes identified by redox proteomics or other techniques to be oxidatively damaged(and likely thereby dysfunctional)in AD brain (and most also in amnestic mild cognitive impairment(aMCI)brains)12,22,2426,34,35,115 are indicated as dashed lines in the figure.1,3-BPG,1,3-bisphosphoglycerate;2-PG,2-phosphoglycerate;3-PG,3-phosphoglycerate;-KG,-ketoglutarate;DHAP,dihydroxyacetone phosphate;F6P,fructose-6-phosphate;FBP,fructose-1,6-bisphosphate;G3P,glyceraldehyde-3-phosphate;G6P,glucose-6-phosphate;OAA,oxaloacetate;PEP,phosphoenolpyruvate.NAtuRe Reviews|NeuROSCIeNCeReviews voluMe 20|MARCH 2019|149aMCI brains or cerebrospinal fluid(CSF)8,14,20.Increased lipid peroxidation(a term explained in Table2)in AD and aMCI brains or CSF and in PCAD hippocampi is further evidenced by rises in the levels of protein-conju-gated 4-hydroxy-2-nonenal(HNE),F2-isoprostanes and F4-isoprostanes8,1113,15,16,1923.Elevated levels of 3-nitro-tyrosine(3-NT),suggestive of damage by peroxyni-trite(Table2),are also observed in AD18,24 and aMCI25.8-Hydroxy-deoxyguanosine(8-OHdG),a biomarker of oxidative damage to DNA(Table2),is also elevated in AD(in both nuclear and mitochondrial DNA)2628,as is oxida-tive damage to RNA29,30.For example,neuritic plaques (rich in fibrillar A42 and A40)and NFTs contain oxidized,glycated and nitrated proteins.Consequences of this increased oxidative and nitrosative damage are likely to include glucose dysmetabolism(see section on oxidative damage below)and loss of ion gradients with resulting impaired action potentials and Ca2+dyshomeostasis.The latter is because oxidative stress is well known to raise intracellular free Ca2+levels,from which several deleterious consequences can follow8.Moreover,oxidative DNA damage can interfere with gene transcription and affect promoter function,which can lead to impaired transcription of essential genes and to mutations.Oxidative RNA damage can impair protein translation,and the damaged RNA can be prematurely degraded,further impairing the synthesis of essential proteins(Table2).Learning and memory deficits,decreased higher executive function and diminished reasoning ability characterize patients with AD,whereas memory defi-cits are a hallmark of aMCI.In both conditions,these altered functions largely originate from synaptic dys-function involving altered synaptic proteomes31,32.A42 oligomers contribute to this synaptic dysfunction,impairing learning and memory31.A42 oligomers also cause oxidative damage to synaptic membranes12,16,and there seems to be an intimate relationship between this oligomer-induced oxidative damage and synaptic dys-function.Indeed,the first pathological insults to neurons in AD and aMCI occur at presynaptic and postsynaptic membranes1,3.Interestingly,large oligomers of A42,which would have difficulty solubilizing in the neu-ronal lipid bilayer,seem relatively non-toxic,whereas small oligomers of A42(for example,dimers or trim-ers that easily enter lipid bilayers)appear highly toxic to synapses33.These considerations support the notion that lipid peroxidation,and perhaps other forms of oxidative damage in synaptic membranes,account for the loss of long-term potentiation and other synaptic functions involved in learning and memory12,15,16,2022,34,35.Dysfunctional glucose metabolism in ADThe brain is an energy-demanding organ and relies heavily on efficient ATP production via glycolysis,the TCA cycle and oxidative phosphorylation7(Fig.1).However,glucose metabolism in AD and aMCI brains is significantly impaired57,9,36.What causes this loss of glucose utilization?Contribution of oxidative damage.Research from our laboratories11,12,34 and many others2,4,8,10 has shown that inefficient glucose utilization(and thus impaired ATP production)and oxidative damage are intimately related.A major contributor to inefficient glucose utilization may well be oxidative modification,which often leads to decreased activity of the enzymes involved in glucose metabolism(Fig.1).The techniques of redox proteomics34 allowed spe-cific oxidatively or nitrosatively modified proteins(that is,PC-modified,protein-bound HNE-modified and/or 3-NT-modified proteins)to be identified in the brain from subjects with late-stage AD,aMCI and PCAD20,24,34,35.For example,redox proteomics of AD brain tissue revealed that in affected brain areas,oxi-dative modification of the glycolytic enzymes aldolase,triosephosphate isomerase(TPI),glyceraldehyde-3-phosphate dehydrogenase(GAPDH),phosphoglyce-rate mutase 1(PGAM1)and-enolase occurs12,34.In addition,oxidative modifications to aconitase(a key ironsulfur-containing enzyme in the TCA cycle),crea-tine kinase(an enzyme that helps neurons to maintain ATP levels)and ATP synthase in brain mitochondria help to explain decreased glucose metabolism and consequent decreased ATP production in the brains of people with aMCI and AD12,25,34.Oxidative dam-age to mitochondrial DNA27,28 might also contribute to impaired energy production,and there has been a suggestion that defects in sirtuin 3(SIRT3)contribute to oxidative damage in AD mitochondria37.Indeed,mitochondrial dysfunction and insulin resistance are intimately related7,36.The consequences of this decreased ATP production in AD and aMCI are profound.For example,decreased ATP will diminish the neurons ability to maintain ionic gradients,hindering production and propagation of action potentials and therefore neurotransmission.Moreover,loss of ion gradients can allow extracellu-lar Ca2+to enter,which can further raise intracellular free Ca2+levels,stimulating Ca2+-dependent endo-nuclease,phospholipase and proteinase activities8,contributing to synaptic dysfunction and eventual neuronal death.Excess Ca2+can saturate the ability of the endoplasmic reticulum(ER)and mitochondria to buffer and cycle Ca2+,causing swelling of the latter with consequent opening of the mitochondrial permeabi-lity transition pore,leading to release of cytochrome c and apoptosis-inducing factor 1,provoking neuronal apoptotic death38.Excess intraneuronal free Ca2+can Redox proteomicsa method for identification of oxidatively modified proteins that most often involves protein separation and digestion,mass spectrometric utilization to sequence the amino acids of the resulting peptides and protein identification and informatics.Table 1|Some biologically important ROS and RNSROSRNSRadical Superoxide,O2 Hydroxyl,OH Peroxyl,RO2 Alkoxyl,RO Nitric oxide,NO Nitrogen dioxide,NO2 Nitrate,NO3Non-radical Hydrogen peroxide,H2O2 Hypochlorous acid,HOCl Organic peroxides,ROOH Peroxynitrite,ONOO Peroxynitrous acid,ONOOH Nitrous acid,HNO2 Nitrosyl cation,NO+Nitrosyl anion,NO Peroxynitrite,ONOO Peroxynitrous acid,ONOOHNote that NO,ONOO and ONOOH are classified as both reactive nitrogen species(RNS)and reactive oxygen species(ROS).For a detailed discussion,see reF.8,from which this table is 2019|voluMe 20 also cause loss of fidelity of microtubule assembly39,with consequent decreased anterograde and retro-grade transport of mitochondria and neurotransmitter vesicles,starving presynaptic terminals of energy and decreasing neurotransmission,which,in turn,leads to synaptic dysfunction,neuronal death and ultimately cognitive dysfunction.mTOR activation and AD.Brain insulin resistance is common in AD7,36,40.One of the mechanisms by which insulin resistance can develop is by activation of the mechanistic target of rapamycin(sometimes called the mammalian target