《线粒体生物学与医学》课程教学课件（Mitochondria Biology and Medicine）7 线粒体生物医学 Mitochondrial associated disorders（AD-PD-T2D，Alzheimer’s disease, AD 阿尔茨海默症）

Mitochondrial dysfunction associated disordersJiangang Long,PH.D.Institute of Mitochondrial Biologyand MedicineXIl'AN Jiaotong University

Mitochondrial dysfunction associated disorders Jiangang Long, PH.D. Institute of Mitochondrial Biology and Medicine XI’AN Jiaotong University

MitochondrialdysfunctionassociateddisordersMitochondrial dysfunction-related diseases:a class of diseasesassociated with mitochondrial oxidative damage and energyimpairment, excluding mitochondrial hereditary diseases.Alzheimer'sdisease(AD)Parkinson's disease(PD)Type2diabetes (TD)Age-relatedmaculardegeneration(AMD)

Mitochondrial dysfunction associated disorders Mitochondrial dysfunction-related diseases: a class of diseases associated with mitochondrial oxidative damage and energy impairment, excluding mitochondrial hereditary diseases. ⚫ Alzheimer’s disease (AD) ⚫ Parkinson’s disease (PD) ⚫ Type 2 diabetes (TD) ⚫ Age-related macular degeneration (AMD) ⚫

Alzheimer's disease,AD阿尔茨海默症

Alzheimer’s disease, AD 阿尔茨海默症

Keypoints Discovery and symptoms of AD, incidence(China)Pathological characteristicsAPP and AβMitochondria and ADOxidative damageDynamicchangesMitochondrialnutrients

Key points  Discovery and symptoms of AD, incidence (China)  Pathological characteristics  APP and Aβ  Mitochondria and AD ◼ Oxidative damage ◼ Dynamic changes ◼ Mitochondrial nutrients

Alzheimer's Disease（(AD）First described by German psychiatrist andneuropathologist Alois Alzheimer in 1906The most common form of dementiaPatientsshowed progressive cognitive decline,including memory, thinking, analysis and judgmentvisual space.emotional and other obstaclesAlzheimer'sdiseaseisthemostcommonneurodegenerative disease in the elderlyDr.Alzheimer

Alzheimer’s Disease (AD) Dr. Alzheimer • First described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 • The most common form of dementia • Patients showed progressive cognitive decline, including memory, thinking, analysis and judgment, visual space, emotional and other obstacles. • Alzheimer's disease is the most common neurodegenerative disease in the elderly

ProfilesofADRonaldReagan(1911-2004)

Ronald Reagan (1911-2004) Profiles of AD

Profiles of ADEstimated26.6millionpeopleworldwidesufferedfromAlzheimer'sin2006EstimatesofChinesepatients:6million（2005)and10million(2020),accountsfor1/4oftheworld'sADpatients.AEastWest2510020265-7475-8485+55-64AgegroupFig.2.Age-specificprevalenceofAD,westversuseastChinaNeuroepidemiology2006;27:177-187DOI:10.1159/000096131

• Estimated 26.6 million people worldwide suffered from Alzheimer's in 2006 • Estimates of Chinese patients: 6 million (2005) and 10 million (2020), accounts for 1/4 of the world's AD patients. Profiles of AD

Characteristics of ADPathologicalmanifestations:- Beta-amyloidprecipitation in cerebral cortexand hippocampus一neurofibrillarytangles(神经纤维缠绕，主要为磷酸化神经元微管蛋白一tau蛋白） is mainly phosphorylated neuron tubulin-tau protein.Related mutant genes (account for less than 10% AD cases):-amyloidprecursorprotein (APP),-presenilins 1,2-Apoe4- Two locigavereplicated evidence of association:onewithinCLu(alsocalled APOJ), encoding clusterin or apolipoprotein J, on chromosome 8theother withinCR1, encoding the complement component (3b/4b) receptor1, on chromosome 1 (Nature Genetics volume 41, (2009)

• Pathological manifestations: – Beta-amyloid precipitation in cerebral cortex and hippocampus – neurofibrillary tangles(神经纤维缠绕，主要为磷酸化神经元微管蛋白－tau蛋 白）is mainly phosphorylated neuron tubulin-tau protein. • Related mutant genes (account for less than 10% AD cases): – amyloid precursor protein (APP), – presenilins 1, 2 – Apoe4 – Two loci gave replicated evidence of association: one within CLU (also called APOJ), encoding clusterin or apolipoprotein J, on chromosome 8 the other within CR1, encoding the complement component (3b/4b) receptor 1, on chromosome 1 (Nature Genetics volume 41, (2009) Characteristics of AD

CharacteristicsofAD-Aβ plaquesHumanAβplaqueNeuNAβPlaqueMergeAPPmice(F,24m)ByLongJG,unpulished

Characteristics of AD -Ab plaques Ab Plaque NeuN Merge APP mice (F,24m) Human Ab plaque By Long JG, unpulished

CellAPPMembraneMoleculeFromAPPtobetaamyloidCelInteriorAPP:Amyloid precursorproteinOSBeta-AmyloidBeta amyloid:Aβ isproduced by thehydrolysis of beta secretase (BACE)andEnzymes- secretase by beta-amyloid proteinBeta-Amyloidprecursor (APP)toform39-42aminoPlaqueacidfragmentsA家National InstituteonAging+

From APP to beta amyloid APP: Amyloid precursor protein Beta amyloid: Aβ is produced by the hydrolysis of beta secretase (BACE) and g- secretase by beta-amyloid protein precursor (APP) to form 39-42 amino acid fragments