Autophagy Dysfunction in Alzheimer's Disease and Dementia

Description

Autophagy Dysfunction in Alzheimer’s Disease and Dementia provides an overview for researchers and clinicians on the mechanisms involved in protein degradation in Alzheimer’s. The book discusses the implication of autophagy dysfunction in these diseases and how it causes degenerated proteins, including aggregated tau and aggregated amyloid protein. Other sections explores the possibilities of potential drug development through autophagy modulation, making this a great resource on the study of how autophagy dysfunction has been linked to the accumulation of misfolded proteins that cause death of neurons in Alzheimer’s and other neurodegenerative diseases. Front Cover Autophagy Dysfunction in Alzheimer’s Disease and Dementia Copyright Dedication Contents Contributors Foreword Preface Acknowledgments Section I: Degradation mechanisms of cells Chapter 1 Degradation mechanisms of cells 1 . Neurons are highly polarized cells with the sophisticated trafficking system 2 . Ubiquitin-proteasome system: UPS 2.1 Molecular mechanism for the ubiquitin-dependent degradation of proteins 2.2 Functional roles of the UPS in neurons 3 . Autophagy-endolysosomal system: APELS 3.1 Lysosome-mediated degradation of cellular macromolecules 3.2 Endocytic pathways to the lysosome 3.3 Endocytic pathways and endosome trafficking in neurons 3.4 Autophagic pathways to the lysosome 3.5 Functional roles of autophagy in neurons 3.6 Rab GTPases involves in autophagosome and endolysosome transport in neurons 4 . Integration of cellular degradation systems References Section II: Lysosomes Chapter 2 Lysosomes-neuronal degeneration in lysosomal storage disorders 1. Lysosomes 2. Lysosomal storage diseases 3. Impairment of lysosomal activity and alteration in the sphingolipid composition of cell membranes: A possible link ... 4. Involvement of mitochondrial impairment in the onset of neurodegeneration in lysosomal storage diseases 5. Involvement of lysosomal impairment in the neuroinflammation References Section III: The autophagic pathways Chapter 3 The autophagy pathway and its key regulators 1 . The autophagy machinery 2 . Key regulators and signaling pathways of autophagy 2.1 Regulation of autophagy by MTOR 2.2 Autophagy regulation by AMPK 2.3 Regulation of autophagy by inositol and calcium signaling 2.4 Autophagy regulation by reactive oxygen species and redox signaling 2.5 Regulation of autophagy by the unfolded protein response 2.6 Regulation of autophagy by transcription factors 2.7 Regulation of autophagy by microRNAs 2.8 Regulation of autophagy by posttranslational and epigenetic modulators 3 . Selective autophagy regulated by autophagic receptors 3.1 Mitophagy 3.2 Aggrephagy 3.3 ER-phagy 4 . Concluding remarks Acknowledgment References Section IV: Amyloid beta protein and autophagy Chapter 4 Basics of amyloid β -protein in Alzheimer’s disease 1 . What is amyloid β ? 2 . Production and formation 2.1 APP 2.2 β -Secretase 2.3 γ -Secretase 2.4 α -Secretase 2.5 A β 40 and A β 42 3 . Aggregation 3.1 Amyloid hypothesis 3.2 Oligomer hypothesis 3.3 Process of A β aggregation 3.4 Soluble low-molecular-weight oligomer 3.5 High-molecular-weight oligomers and off-pathways 4 . Regulation of A β concentration in the brain 5 . Decomposition and excretion 5.1 Decomposition 5.2 Excretion 5.3 Normal function of A β 6 . Relationship between A β and disease (including gene mutation) 6.1 Sporadic AD 6.2 FAD and genetic mutation 6.2.1 Gene mutation that enhances A β production 6.2.2 Gene mutation that changes the production ratio of highly cohesive A β 42 6.2.3 Gene mutations that alter aggregation potential 6.3 Down syndrome 7 . Intervention strategy 7.1 Secretase activity regulator 7.2 A β aggregation inhibitor 7.3 Immunotherapy 7.4 Other strategies 7.5 Summary of intervention strategies and the future References Chapter 5 Molecular linkages among A β, tau, impaired mitophagy, and mitochondrial dysfunction in Alzheimer’s disease 1 . Introduction 2 . Mitochondrial dysfunction 2.1 Mitochondria play fundamental roles in development and activities of neurons 2.2 Mitochondrial dysfunction is an early feature of AD 2.3 Interactions of mitochondria with A β and tau 3 . Defective mitophagy in AD 3.1 Molecular mechanisms of mitophagy 3.2 Defective mitophagy in AD 4 . Mitochondrial dysfunction and defective mitophagy at the circuit and behavioral level 5 . Future research Acknowledgments Competing interests References Chapter 6 Endocytosis in β-amyloid biology and Alzheimer’s disease 1. Introduction 2. The flavors of endocytosis in the brain 3. The MO(F) of Aβ 4. Endocytosis in a phagocytic world 5. Adding a modifier, a new world for endocytosis in the AD brain 6. Endocytosis in a starry world 7. Exploiting endocytosis for therapeutic gain 8. Recycling full circle, a summary Acknowledgments Disclosures References Section V: Autophagy and tau protein Chapter 7 Autophagy and tau protein 1 . Introduction 2 . Tau protein 2.1 Physiological functions of tau 2.2 Posttranslational modifications of tau 2.2.1 Phosphorylation of tau protein 2.2.2 Ubiquitination of tau protein 2.2.3 Acetylation of tau protein 2.2.4 Nitration 2.2.5 Glycosylation of tau 2.2.6 Truncation of tau protein 2.2.7 Tau toxicity 3 . Autophagy 3.1 Concept of autophagy 3.2 Initiation of autophagy 3.3 Nucleation of phagophores 3.4 Elongation and closure 3.5 Fusion of lysosomes 4 . Disturbance of the autophagy-lysosome system in AD and related disorders 4.1 Disruption of the autophagy-lysosome system in AD 4.2 Sporadic inclusion of body myositis and tau and A β 4.3 Tau and A β can induce autophagy dysfunction 5 . Tau degradation pathway 6 . Mitophagy and tau 7 . Diabetes, tau, and autophagy 8 . Propagation of tau by the disruption of autophagy 8.1 Pathways of pathological tau protein secretion 8.1.1 Direct secretion of tau through the cell membrane 8.1.2 Tau is secreted into ectosomes 8.1.3 Secretion of tau by exosomes and organelle hitchhiking 8.1.4 Tau seeds move between cells via tunneling nanotubes that directly connect the cytoplasm of two adjacent cells 8.2 Propagation of tau by the disruption of autophagy 9 . Potential of autophagy modulators as a treatment for AD 10 . Conclusion Acknowledgments References Chapter 8 BAG3 promotes tau clearance by regulating autophagy and other vacuolar-dependent degradative processes 1 . Introduction 2 . BAG3 protein 2.1 BAG3 mediated tau degradation 2.2 Mechanisms of BAG3-mediated tau degradation 3 . Summary Acknowledgments References Chapter 9 Tau propagation and autophagy 1 . Introduction 2 . Tau propagation mechanisms 2.1 Experimental methods for Tau propagation 2.1.1 In vitro Tau propagation Self-assembly of Tau Seed-dependent Tau propagation Seed-dependent Tau propagation using a cell-based assay 2.1.2 In vivo Tau propagation 2.2 Potential routes for the intercellular spread of Tau aggregates 2.2.1 Trans-synaptic Tau propagation 2.2.2 Exo-synaptic Tau propagation 2.2.3 Extracellular Tau propagation 2.2.4 Tau propagation by tunneling nanotubes (TNTs) 3 . Autophagic impairment promotes Tau aggregation 3.1 Macroautophagic dysfunction in tauopathies 3.2 CMA dysfunction in tauopathies 3.3 Microautophagic dysfunction in tauopathies 4 . Pharmacological agents modulating Tau propagation 4.1 Autophagic modulators attenuated Tau propagation 4.2 Lithium-induced autophagic promotion of aggregated Tau clearance 5 . Conclusion Author contributions Conflict of interest References Section VI: Autophagy and pathology in Alzheimer’s disease Chapter 10 Granulovacuolar degeneration in neurodegeneration 1. Introduction 2. Neuropathological features of granulovacuolar degeneration (GVD) in neurons 3. What kind of organelle are GVBs? 4. GVB-like structures in oligodendroglia in multiple system atrophy Acknowledgment References Chapter 11 Autophagy dysfunction in skeletal myopathies: Inclusion body myositis and Danon disease 1 . Autophagy and autophagic vacuoles 2 . Autophagic vacuolar myopathy 2.1 Pompe disease 2.2 Rimmed vacuolar myopathy 2.3 AVSF myopathy 3 . Inclusion body myositis 3.1 Outline of the disease 3.2 Clinical features 3.3 Muscle pathological features 3.4 Pathogenesis and pathomechanism 3.4.1 Mechanism of degeneration: Homology of Alzheimer’s disease 3.4.2 Abnormality in proteolytic pathway 3.4.3 Abnormality in immunological system 4 . Danon disease 4.1 Outline of the disease 4.2 Epidemiology 4.3 Pathogenesis and pathomechanism 4.4 Clinical features 4.5 Muscle pathological features 4.6 Diagnosis and differential diagnosis 4.7 Important differential diagnosis: XMEA 4.8 Therapy and prognosis 5 . Conclusion References Section VII: Autophagy and other disorders causing dementia Chapter 12 Autophagy in Lewy body diseases and multiple system atrophy 1 . Introduction 2 . Autophagy 3 . Lewy body diseases 3.1 Clinical features of Lewy body diseases 3.2 Pathological features of Lewy body diseases 3.3 Pathological staging systems for Lewy body diseases 3.4 Neuroprotective role of Lewy bodies in Lewy body diseases 3.5 α -Synuclein as a substrate for autophagy 3.6 Impairment of autophagy in the brain of individuals with Lewy body diseases 3.7 Impairment of autophagy in PD—Is it a primary or secondary event? 4 . MSA 4.1 Clinical and pathological features of MSA 4.2 Impairment of autophagy in the brain of individuals with MSA 4.3 Impairment of autophagy in MSA—Is it a primary or secondary event? 4.4 Current challenges and future directions in autophagy of synucleinopathies 5 . Conclusions Acknowledgments References Chapter 13 Autophagy and Huntington’s disease 1 . Introduction 2 . Macroautophagy in HD 2.1 Alfy 2.2 p62 2.3 NBR1 2.4 Optineurin 2.5 Tollip 3 . Physiological function of Htt in autophagy 4 . Autophagy: A therapeutic target 5 . Conclusion References Section VIII: Drug discovery in Alzheimer’s disease by modulating autophagy Chapter 14 Drug discovery in Alzheimer’s disease by regulating autophagy 1 . Introduction 2 . Drugs that induce autophagy 2.1 Direct mTORC inhibitors 2.1.1 Rapamycin 2.1.2 Rapamycin analogs 2.2 Other mTORC-dependent autophagy inducers 2.2.1 Methylene blue 2.2.2 Curcumin 2.2.3 Latrepirdine 2.2.4 β -asarone 2.2.5 Oleuropein aglycone (polyphenol) 2.2.6 Omega-3 fatty acids 2.3 AMPK activator 2.3.1 Metformin 2.3.2 Trehalose 2.3.3 Resveratrol 2.3.4 5-Aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) 2.3.5 Arctigenin 2.3.6 Statins 2.4 IMPase, IP 3 inhibitors 2.4.1 Lithium 2.5 Carbamazepine 2.6 Imidazoline receptor agonists (reducing cAMP) 2.6.1 Clonidine and rilmenidine 2.7 Drugs targeting TFEB 2.7.1 About TFEB 2.7.2 Flubendazole and bromhexine 2.7.3 Fisetin 2.7.4 Curcumin analog 2.7.5 Optogenetic TFEB inducer 2.8 Increased lysosome/autolysosome acidification and reduce autophagosome accumulation 2.8.1 Nicotinamide 2.9 JNK1/Bcl-2/PI3K activator 2.9.1 l -NAME 2.10 Calcium channel antagonist 2.10.1 Nitrendipine, and nilvadipine 2.11 VPS34 activator 2.11.1 Memantine 2.12 Atg-dependent pathway 2.12.1 SMER28 2.12.2 Spermidine 2.12.3 Tetrahydrohyperforin 2.13 ATP6V0A1 enhancer 2.13.1 Rifampicin 2.14 P300 inhibitors (tau acetylation inhibitors) 2.14.1 SMDC37892 2.14.2 Cilostazole 2.15 Multiple mechanisms 2.15.1 Vitamin D 2.16 ABL1 inhibitor 2.16.1 Nilotinib and bosutinib 2.17 Others 2.17.1 GTM-1 2.17.2 Bexarotene 2.17.3 Lonafarnib 2.17.4 ROCK inhibitor 2.18 Gene therapies 3 . Caspase activation and autophagy 4 . Conclusion References Chapter 15 Drug discovery in Alzheimer’s disease using metal chelators: Warning toward their usage 1 . Introduction 2 . Abnormal metals in AD patients 3 . Clioquinol and SMON (subacute myelo-optico-neuropathy) 3.1 SMON (subacute myelo-optico-neuropathy) 3.2 In vivo concentration of clioquinol is extremely important 3.3 Molecular action of clioquinol 3.3.1 Metal chelating activity 3.3.2 Its effects on autophagy 3.3.3 Its effect on Trk-neurotrophin signaling 4 . Conclusion Acknowledgments Conflict of interest References Chapter 16 Development of autophagy enhancers for Parkinson’s disease therapy 1 . Features of Parkinson’s disease 2 . Current PD therapy 3 . α -Synuclein accumulation in PD 4 . Autophagy impairment in PD 5 . Targeting macroautophagy for potential PD therapy 5.1 Targeting mTOR 5.2 Targeting AMP-activated protein kinase (AMPK) 5.3 Targeting ULK1 and VPS34 6 . Targeting lysosome for potential PD therapy 6.1 Targeting TFEB 6.2 Targeting glucocerebrosidase (GCase) 6.3 Targeting CMA 6.4 Clinical trials of nilotinib for PD therapy 7 . Conclusions and future perspectives Acknowledgment References Index Back Cover