《线粒体生物学与医学》课程教学课件（Mitochondria Biology and Medicine）5 Mitochondrial Metabolic Disorder in Alzheimer’s Disease - Targeting Mitochondria for Diagnosis and Prevention

AUDTE21-学与技Mitochondrial Metabolic Disorder in Alzheimer's Disease:Targeting Mitochondria for Diagnosis and PreventionJiangang Longjglong@mail.xjtu.edu.cnInstitute of Mitochondrial Biology and MedicineIMBMXi'an Jiaotong University, Xi'an

Mitochondrial Metabolic Disorder in Alzheimer’s Disease: Targeting Mitochondria for Diagnosis and Prevention Jiangang Long jglong@mail.xjtu.edu.cn Institute of Mitochondrial Biology and Medicine, IMBM Xi’an Jiaotong University, Xi’an

糖尿病在中国迅速发展Diabetes in China 2010113.9 million Chinese adults with diabetes (11.6%)493.4 million with prediabetes (50.1%)ADiabetesBPrediabetes30.080.025.0MenWomerde060.020.015.040.010.020.05.00.00.018-2950-5960-69≥7030-3940-4918-2930-3940-4950-5960-69≥70Age, yAge,yJAMA.2013:310(9):948-958

糖尿病在中国迅速发展 Diabetes in China 2010 • 113.9 million Chinese adults with diabetes (11.6%) • 493.4 million with prediabetes (50.1%) JAMA. 2013;310(9):948-958

China: An Aging Society19502010China's60+PopulationMalesFemales2010-2050437M248M20502100167MSooreerCehetXutioesPogulatioeDividionMTT.ALa,200D2010202020504(millions)Age and gender structure of China,1950,2010,2050, and2100.Source: UNDESA(2011)3

China: An Aging Society 3

AD: a systemic metabolic disease·AD affects boththeCNS andperipheryBaselineRisk·ADtransgenicmiceMitochondrial Genes(COX,etc)NuclearGenes·develop liver insulinAPOE4,TOMM40,etc)InsulinResistance (+)resistanceExercise (-)Potential risk·increased susceptibilitytoAdvancingage (+)modifiersHeart healthydiet-induced obesity anddiet (-)Vascularevents (+)Education (-)glucose intoleranceMidlife obesity (+).Liverand skeletalmuscleOther/Unknowinsulin resistanceindiabeticob/ob micewasexacerbatedbyCumulativelate-onsetADriskcrossbreedingwithAPP23miceBiochimBiophysActa.2014

AD: a systemic metabolic disease • AD affects both the CNS and periphery • AD transgenic mice • develop liver insulin resistance • increased susceptibility to diet-induced obesity and glucose intolerance • Liver and skeletal muscle insulin resistance in diabetic ob/ob mice was exacerbated by crossbreeding with APP23 mice Biochim Biophys Acta. 2014

糖尿病与老年痴呆病存在关联Cognitive function and diabetesCognitivefunctionwasimpaired in diabeticsubjects.(Archives ofphysical medicine andpancreaticncretininsulineffectrehabilitation.2013)secretionpancreaticucagon？secretionPUDiabetes is amajorriskfactorforcarbohydratedelivery&HYPERGLYCEMIAabsorptionneurodegenerative diseases suchas AD.(Neurology.2011)peripheralhepaticglucoseglucoseuptakeHyperinsulinemia and hyperlipidemia arisingnroductianfromdiabeteshavebeenlinkedtoneuronalinsulinresistanceEndocrinology,2011;Neuropharmacology,2009)

糖尿病与老年痴呆病存在关联 Cognitive function and diabetes • Cognitive function was impaired in diabetic subjects. (Archives of physical medicine and rehabilitation. 2013 ) • Diabetes is a major risk factor for neurodegenerative diseases such as AD. (Neurology. 2011) • Hyperinsulinemia and hyperlipidemia arising from diabetes have been linked to neuronal insulin resistance Endocrinology,2011; Neuropharmacology,2009)

Cognitive dysfunction and Metabolic DisorderFattyAcidGlucosCYTOPLASMLipolysisI.GlucoseMetabolisminADAcetyl-CoAATPLipogenesisLA.GlucoseuptakedeficitGlycolysisB.InsulinresistanceoPyruvateC. GlycosylationH,OATP?Acetyl-CoAOHeH202TCACycleADPI.Lipid MetabolisminAD?AcetoacetateeA.LipiddysregulationasanearlysignalKetogenesisRespirationB.LipogenesisC. LipolysisNADHFADHβ-HBAcetoneD.Hepatic inflammatoryfactorCYTOPLASMMITOCHONDRIAenhancesketogenesisCOAlternativeenergyfuelUnpublishedIll.MitochondriaattheCoreofMetabolisminADA.MitochondrialdysfunctionprecedesmetabolicdisorderB.Mitochondria mediate pathologic impairment during AD progressionC.Mitochondrial remodelingD.Mitochondria-launched inflammation and oxidative stress during thepathogenesisE.Mitochondrial metabolic disorder links nutritional imbalance to neural DNA epigenetic remodeling

Cognitive dysfunction and Metabolic Disorder I. Glucose Metabolism in AD A. Glucose uptake deficit B. Insulin resistance C. Glycosylation II. Lipid Metabolism in AD A. Lipid dysregulation as an early signal B. Lipogenesis C. Lipolysis D. Hepatic inflammatory factor enhances ketogenesis III. Mitochondria at the Core of Metabolism in AD A. Mitochondrial dysfunction precedes metabolic disorder B. Mitochondria mediate pathologic impairment during AD progression C. Mitochondrial remodeling D. Mitochondria-launched inflammation and oxidative stress during the pathogenesis E. Mitochondrial metabolic disorder links nutritional imbalance to neural DNA epigenetic remodeling Unpublished

西安交通大学ResearchStrategiesXIANJIAOTONGUNIVERSITYMonitoringtimecourse of pathogenesisMultiomicsstudyonMitochondriafunctionClinical biopsyInvitro&InvivomodelsMitochondriadynamics&metabolomicsstudy20002500300Beneficial effectsTime (s)MitochondrialBiomarkers&Biochemistry&Molecularoncognition&therapeutichomoestasisbiology&FunctionalmetabolismtargetsanalysisNutrients.NaturalproductsMedicineMolecularscreenandintervention

Mitochondria dynamics & metabolomics study Biochemistry & Molecular biology& Functional analysis Biomarkers & therapeutic targets Nutrients, Natural products, Medicine Mitochondrial homoestasis Multiomics study on Mitochondria function Beneficial effects on cognition & metabolism Clinical biopsy In vitro & In vivo models Monitoring time course of pathogenesis Molecular screen and intervention Research Strategies

Points to be addressed: Hyperglycemia- induced neuronal mitochondrialdysfunction and insulin resistance: Peripheral lipid/glucose metabolic remodeling inAPP/ps1 mouse: Biomarkers for early diagnosisofAD: Target mitochondria by mitochondrial nutrients:Hydroxytyrosol and Hydrogen

Points to be addressed • Hyperglycemia- induced neuronal mitochondrial dysfunction and insulin resistance • Peripheral lipid/glucose metabolic remodeling in APP/PS1 mouse: Biomarkers for early diagnosis of AD • Target mitochondria by mitochondrial nutrients: Hydroxytyrosol and Hydrogen

Impaired Insulin Signaling/Mt dysfunction in AD Brain(postmortem samples)NDADNDADNDADNDMCI=150AKTADGSK-3αsaruerojo%GSK-3β100p70S6KActin50-eee1IVMDH100NDAD50-AKTGSK-3aGSK-3βp70JiangangLong,etal.JournalofAlzheimer'sDisease,2012

Impaired Insulin Signaling/Mt dysfunction in AD Brain （postmortem samples) + * + + ++ ** * Jiangang Long, et al. Journal of Alzheimer's Disease, 2012

Mitochondrialdysfunctionprecedesinsulinresistanceinneurondegeneration underhyperglycemiaHighGlucoseMtdysfunctionP-AMPK/AKTMtcomponentlossInsulinresistanceNeuronal ImpairmentandMetabolicDisorderYunhuaPeng,etal.JournalofNeurochemistry,2016

Neuronal Impairment and Metabolic Disorder High Glucose p-AMPK/AKT ↓ Mt dysfunction Mt component loss Insulin resistance Mitochondrial dysfunction precedes insulin resistance in neuron degeneration under hyperglycemia Yunhua Peng, et al. Journal of Neurochemistry, 2016