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AUTOPHAGY DYSFUNCTION IN ALZHEIMER’S DISEASE AND DEMENTIA This page intentionally left blank AUTOPHAGY DYSFUNCTION IN ALZHEIMER’S DISEASE AND DEMENTIA Edited by TADANORI HAMANO Associate Professor, Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan Clinical Professor, Department of Neurology, University of Fukui Hospital, Fukui, Japan TATSURO MUTOH Professor, Department of Neurology and Neuroscience, Fujita Health University Hospital, Toyoake-City, Aichi, Japan Department of Internal Medicine Fujita Health University Chubu International Airport Clinic, Tokoname-City, Aichi, Japan Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2022 Elsevier Inc. All rights reserved. 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Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN 978-0-323-89906-2 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals Back cover image: Figure S2 (part B) reprinted from Bradlee L. Heckmann, Brett J.W. Teubner, Bart Tummers, Emilio Boada-Romero, Lacie Harris, Mao Yang, Clifford S. Guy, Stanislav S. Zakharenko, and Douglas R. Green. “LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease” in Cell, Vol 178, Issue 3, 25 July 2019, pp 536-551. e14, with permission from Elsevier. Publisher: Nikki Levy Acquisitions Editor: Joslyn Chaiprasert-Paguio Editorial Project Manager: Kristi Anderson Production Project Manager: Maria Bernard Cover Designer: Christian Bilbow Typeset by STRAIVE, India Dedication This book is dedicated to Late Professor Masaru Kuriyama, University of Fukui, Japan. This page intentionally left blank Contents Contributors xiii Foreword xvii Preface xix Acknowledgments xxi SECTION I Degradation mechanisms of cells 1. Degradation mechanisms of cells 3 Asako Otomo and Shinji Hadano 1. Neurons are highly polarized cells with the sophisticated trafficking system 3 2. Ubiquitin-proteasome system: UPS 4 3. Autophagy-endolysosomal system: APELS 8 4. Integration of cellular degradation systems 18 References 19 SECTION II Lysosomes 2. Lysosomes-neuronal degeneration in lysosomal storage disorders 25 Giulia Lunghi, Emma Veronica Carsana, Nicoletta Loberto, Sandro Sonnino, and Massimo Aureli 1. Lysosomes 25 2. Lysosomal storage diseases 26 3. Impairment of lysosomal activity and alteration in the sphingolipid composition of cell membranes: A possible link with the onset of neuronal damage in LSD 31 4. Involvement of mitochondrial impairment in the onset of neurodegeneration in lysosomal storage diseases 35 5. Involvement of lysosomal impairment in the neuroinflammation 38 References 40 SECTION III The autophagic pathways 3. The autophagy pathway and its key regulators 47 Tetsushi Kataura, Nobutaka Hattori, and Shinji Saiki 1. The autophagy machinery 47 2. Key regulators and signaling pathways of autophagy 49 vii viii Contents 3. Selective autophagy regulated by autophagic receptors 58 4. Concluding remarks 61 Acknowledgment 62 References 62 SECTION IV Amyloid beta protein and autophagy 4. Basics of amyloid β-protein in Alzheimer’s disease 73 Azusa Sugimoto and Kenjiro Ono 1. What is amyloid β? 73 2. Production and formation 74 3. Aggregation 75 4. Regulation of Aβ concentration in the brain 78 5. Decomposition and excretion 78 6. Relationship between Aβ and disease (including gene mutation) 79 7. Intervention strategy 82 References 85 5. Molecular linkages among Aβ, tau, impaired mitophagy, and mitochondrial dysfunction in Alzheimer’s disease 91 Tomas Schmauck-Medina, Thale D.J.H. Patrick-Brown, Shi-qi Zhang, Alexandra Gilbert, and Evandro F. Fang 1. Introduction 91 2. Mitochondrial dysfunction 94 3. Defective mitophagy in AD 98 4. Mitochondrial dysfunction and defective mitophagy at the circuit and behavioral level 101 5. Future research 103 Acknowledgments 103 Competing interests 104 References 104 6. Endocytosis in β-amyloid biology and Alzheimer’s disease 111 Bradlee L. Heckmann and Douglas R. Green 1. Introduction 111 2. The flavors of endocytosis in the brain 112 3. The MO(F) of Aβ 115 4. Endocytosis in a phagocytic world 117 Contents ix 5. Adding a modifier, a new world for endocytosis in the AD brain 120 6. Endocytosis in a starry world 124 7. Exploiting endocytosis for therapeutic gain 125 8. Recycling full circle, a summary 126 Acknowledgments 127 Disclosures 127 References 127 SECTION V Autophagy and tau protein 7. Autophagy and tau protein 135 Tadanori Hamano and Yoshinori Endo 1. Introduction 135 2. Tau protein 137 3. Autophagy 141 4. Disturbance of the autophagy-lysosome system in AD and related disorders 145 5. Tau degradation pathway 148 6. Mitophagy and tau 150 7. Diabetes, tau, and autophagy 151 8. Propagation of tau by the disruption of autophagy 151 9. Potential of autophagy modulators as a treatment for AD 153 10. Conclusion 153 Acknowledgments 154 References 154 8. BAG3 promotes tau clearance by regulating autophagy and other vacuolar-dependent degradative processes 159 Changyi Ji, Heng Lin, and Gail V.W. Johnson 1. Introduction 159 2. BAG3 protein 161 3. Summary 167 Acknowledgments 169 References 169 9. Tau propagation and autophagy 173 Mohammad Nasir Uddin, Shotaro Shimonaka, and Yumiko Motoi 1. Introduction 173 2. Tau propagation mechanisms 174