Alzheimer’s disease is the most common cause of age-related dementia. Alzheimer’s disease presents with irreversible cognitive decline, which commences as insidious short-term memory dysfunction and gradually spreads to other cognitive domains, rendering patients mute and non-ambulatory after 10-15 years of progressive course. Unfortunately, there are neither effective preventive measures nor efficacious treatments available for this devastating disease. Such a situation undoubtedly calls for the diversification of druggable targets for Alzheimer’s disease and a search for poly-targets or drug combination therapeutic strategies. Contributed by an assembly of clinicians and translational and basic research scientists, this book intends to provide an overview of the current state and future perspectives of Alzheimer’s disease drug discovery. It covers the underlying pathogenic mechanisms of Alzheimer’s disease and provides a review of Aβ amyloid- and τ protein-targeted immunotherapies, and peptide inhibitors for anti-Aβ amyloidosis. In addition, it also examines therapeutic potentials of various Alzheimer’s disease drug targets such as brain metal homeostasis, protein kinase C, the blood-brain barrier, epigenetic therapies, as well as discusses chimeric conjugates, multifunctional ligands, and natural products as interventional approaches. This book will be valuable to healthcare professionals caring for patients, researchers and interested readers as it will provoke thoughts about identifying novel and more efficacious therapeutic agents for Alzheimer’s disease and related dementias.

Contents

• Foreword
• Preface
• List of Contributors
• 1. Alzheimer’s Disease: Etiology, Neuropathology and Pathogenesis
  Olivia Sheppard and Michael Coleman.
  • INTRODUCTION
  • ETIOLOGY
  • NEUROPATHOLOGY
  • PATHOGENESIS
  • CONCLUSION
  • REFERENCES
• 2. Immunotherapy Targeting Amyloid-β Peptides in Alzheimer’s Disease
  Silvia Zampar and Oliver Wirths.
  • INTRODUCTION
  • Aβ GENERATION AND AMYLOID CASCADE HYPOTHESIS
  • MECHANISM AND PRINCIPLES OF (AMYLOID-β) IMMUNOTHERAPY
  • ACTIVE AMYLOID-β-DIRECTED IMMUNOTHERAPIES
  • CONCLUSION
  • REFERENCES
• 3. Amyloid β-Targeted Inhibitory Peptides for Alzheimer’s Disease: Current State and Future Perspectives
  Safura Jokar, Saeedeh Khazaei, Xaniar Esmailzadeh Gameshgoli, Mona Khafaji, Behnam Yarani, Mohammad Sharifzadeh, Davood Beiki, and Omid Bavi.
  • INTRODUCTION
  • PEPTIDIC INHIBITORS
  • PEPTIDE LIBRARY SCREENING
  • THE CURRENT STATE AND FUTURE DIRECTIONS OF Aβ INHIBITORY PEPTIDES IN ALZHEIMER’S DISEASE
  • CONCLUSION
  • REFERENCES
• 4. Tau Protein-Targeted Therapies in Alzheimer’s Disease: Current State and Future Perspectives
  Ryszard Pluta and Marzena Ułamek-Kozioł.
  • INTRODUCTION
  • SUBSTANCES PREVENTING TAU PROTEIN POST-TRANSLATIONAL CHANGES
  • SUBSTANCES THAT PREVENT MICROTUBULE DESTABILIZATION BY AMYLOID
  • SUBSTANCES THAT PREVENT TAU PROTEIN AGGREGATION
  • IMMUNOTHERAPY AGAINST TAU PROTEIN
  • FUTURE PERSPECTIVES
  • CONCLUSION
  • REFERENCES
• 5. Targeting Metal Homeostasis as a Therapeutic Strategy for Alzheimer’s Disease
  Antonietta Vilella, Eleonora Daini, Chiara A. De Benedictis, and Andreas M. Grabrucker.
  • INTRODUCTION
  • METALS AND THE AMYLOID PRECURSOR PROTEIN
  • NUTRITIONAL INTERVENTIONS
  • TARGETED INTERVENTIONS: DELIVERY OF METAL-ATTENUATING COMPOUNDS
  • TARGETED INTERVENTIONS: DELIVERY OF TRACE METALS
  • CONCLUSION
  • REFERENCES
• 6. Atypical Protein Kinase C Hyperactivity in Insulin-Resistant and Insulin-Sensitive Forms of Alzheimer’s Disease: A Potential Therapeutic Target
  Robert V. Farese, Mark A. Kindy, and Mini P. Sajan.
  • INTRODUCTION
  • THE ESSENTIAL ROLE OF BACE1 IN THE PATHOGENESIS OF AD
  • SYSTEMIC VERSUS BRAIN INSULIN RESISTANCE IN DIABETES-ASSOCIATED AND NONDIABETIC AD
  • INSULIN RECEPTOR DOWNREGULATION IN OBESITY/T2DM AND AD
  • HYPERINSULINEMIA IN INSULIN-RESISTANT FORMS OF OBESITY AND T2DM AS A RISK FACTOR FOR AD
  • EFFECTS OF DAG-SENSITIVE PKCs (α,δ,ε) VERSUS aPKC-λ/ι ON BACE1 AND AD
  • aPKC INHIBITORS
  • aPKC REQUIREMENTS FOR MEMORY FUNCTION
  • aPKC ACTIVATORS
  • CONTROL OF BACE1 TRANSCRIPTION BY NFκB
  • CONCLUSION
  • REFERENCES
• 7. Modeling the Blood–Brain Barrier to Understand Drug Delivery in Alzheimer’s Disease
  Joanna M. Wasielewska, Juliana C Da Silva Chaves, Anthony R. White, and Lotta E. Oikari.
  • INTRODUCTION
  • ALZHEIMER’S DISEASE RELATED CHANGES IN THE BBB
  • DIFFERENCES BETWEEN ANIMAL AND HUMAN BBB AND IMPLICATIONS TO DRUG DELIVERY
  • BBB IN VITRO CELL MODELS
  • IN VITRO CULTURE PLATFORMS FOR MODELING OF BBB STRUCTURE AND DRUG DELIVERY
  • ENHANCING DRUG DELIVERY IN ALZHEIMER’S DISEASE THROUGH IN VITRO MODELS OF BBB—CHALLENGES AND FUTURE PERSPECTIVES
  • CONCLUSION
  • REFERENCES
• 8. Blood–Brain Barrier Degradation and the Implication of SPARC Protein as a Potential Therapeutic Target for Alzheimer’s Disease
  Alexander Pilozzi, Caitlin Carro, Michael Whalen, and Xudong Huang.
  • INTRODUCTION
  • THE BBB IN AD
  • SECRETED PROTEIN ACIDIC AND RICH IN CYSTEINE
  • FUTURE DIRECTIONS
  • CONCLUSION
  • REFERENCES
• 9. The Therapeutic Potential of Epigenetic Modifications in Alzheimer’s Disease
  Enric Bufill, Roser Ribosa-Nogué, and Rafael Blesa.
  • INTRODUCTION
  • EPIGENETIC CHANGES AND AD
  • EPIGENETIC THERAPIES IN AD
  • CONCLUSION
  • REFERENCES
• 10. Chimeric Conjugates for Alzheimer’s Disease
  Illham Dhala, Tabassum Khan, and Arati Prabhu.
  • INTRODUCTION
  • DISEASE AND PATHOLOGY
  • CURRENT LINE OF TREATMENT
  • RATIONALE FOR CHIMERIC CONJUGATES
  • CONCLUSION
  • REFERENCES
• 11. Multifunctional Ligand Approach: Search for Effective Therapy Against Alzheimer’s Disease
  Anna Pasieka, Dawid Panek, and Barbara Malawska.
  • INTRODUCTION
  • MULTITARGET LIGANDS APPROACH
  • MULTIFUNCTIONAL AGENTS FOCUSING ON DISEASE-MODIFYING TARGETS: Aβ AND OTHERS
  • MULTIFUNCTIONAL AGENTS FOCUSING ON DISEASE-MODIFYING TARGETS: TAU PROTEIN AND OTHERS
  • MULTIFUNCTIONAL AGENTS FOCUSING ON SYMPTOMATIC THERAPIES WITH ADDITIONAL BENEFICIAL PROPERTIES
  • MULTIFUNCTIONAL AGENTS FOCUSING ON VARIOUS DISEASE-MODIFYING AND SYMPTOMATIC THERAPIES
  • CONCLUSION
  • REFERENCES
• 12. Natural Products for Neurocognitive Disorders
  Adriana Servello, Vincenzo Leccese, and Evaristo Ettorre.
  • INTRODUCTION
  • GINKGO BILOBA
  • BACOPA
  • CURCUMIN
  • QUERCETIN
  • KAEMPFEROL
  • CAPSAICIN
  • BERBERINE
  • CONCLUSION
  • REFERENCES

Alzheimer’s Disease: Drug Discovery

ISBN: 978-0-6450017-0-9

DOI: https://dx.doi.org/10.36255/exonpublications.alzheimersdisease.2020

Edited by

Xudong Huang, PhD, Neurochemistry Laboratory, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA

Published by

Exon Publications, Brisbane, Australia

Copyright© 2020 Exon Publications

Copyright of individual chapters belongs to the respective authors. The authors grant unrestricted publishing and distribution rights to the publisher. The electronic versions of the chapters are published under Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). https://creativecommons.org/licenses/by-nc/4.0/. Users are allowed to share and adapt the chapters for any non-commercial purposes as long as the authors and the publisher are explicitly identified and properly acknowledged as the original source. The book in its entirety is subject to copyright by the publisher. The reproduction, modification, replication and display of the book in its entirety, in any form, by anyone, for commercial purposes are strictly prohibited without the written consent of the publisher.

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First Published in December 2020

Printed in Australia