Developing Therapeutics for Alzheimer's Disease

Progress and Challenges
 
 
Academic Press
  • 1. Auflage
  • |
  • erschienen am 27. Mai 2016
  • |
  • 676 Seiten
 
E-Book | ePUB mit Adobe DRM | Systemvoraussetzungen
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978-0-12-802164-4 (ISBN)
 

Developing Therapeutics for Alzheimer's Disease: Progress and Challenges provides a thorough overview of the latest advances toward the development of therapeutics for Alzheimer's disease, along with the major hurdles that still must be overcome and potential solutions to these problems. Despite the lack of progress toward developing therapeutics that can slow or stop the progression of this disease, important discoveries have been made and many promising approaches are advancing in preclinical studies and clinical trials. This book outlines the special challenges related to specific targets and approaches, while presenting a realistic, comprehensive and balanced view of drug discovery and development in this area.

Written by international leaders in the field, the book assesses prospects for the emergence of effective agents and allows readers to better understand the challenges, failures, and future potential for research in Alzheimer's disease. This book is a valuable resource to academic scientists carrying out translational research in Alzheimer's disease, industrial scientists engaged in Alzheimer's drug discovery, executives in biopharmaceutical companies making strategic decisions regarding the direction of internal research and potential outside partnerships, and graduate-level students pursuing courses on Alzheimer's therapeutics.


  • Provides a realistic but promising assessment of the potential of various therapeutic approaches to Alzheimer's disease
  • Focuses primarily on neuroprotective agents and cognitive enhancers, as well as approaches to targeting the amyloid B-peptide, tau and Apolipoprotein E
  • Discusses alternative approaches, preclinical and clinical development issues, related biomarkers and diagnostics, and prevention and nonpharmacological approaches
  • Englisch
  • San Diego
  • |
  • USA
Elsevier Science
  • 22,38 MB
978-0-12-802164-4 (9780128021644)
0128021640 (0128021640)
weitere Ausgaben werden ermittelt
  • Cover
  • Title Page
  • Copyright Page
  • Dedication
  • Contents
  • List of Contributors
  • Foreword
  • Preface
  • Chapter 1 - The Complex Pathways to Mechanism-Based Therapeutics in Alzheimer's Disease
  • Introduction
  • The mechanistic study of Alzheimer's disease melds basic and applied research
  • Alzheimer's disease as a prototype for the molecular elucidation of a chronic brain disorder
  • The driving forces that underlie AD research
  • The Quest for Scientific Clarity
  • The Personal Tragedy of Alzheimer's Disease
  • The Societal Crisis of Alzheimer's Disease
  • The Competition of Ideas and Findings: A Brief Perspective on "BAPtists Versus TAUists"
  • Elucidating the AD mechanism: biochemical pathology, then genetics
  • The first genetic clues to the etiology of AD
  • The discovery of apolipoprotein E4 as the major genetic risk factor for AD
  • Presenilin as the site of mutations causing aggressive, early-onset AD
  • The discovery of presenilin function supports a mechanistic hypothesis of AD initiation
  • Relationship of Aß accumulation to tau alteration and neurofibrillary degeneration
  • An increasingly recognized role for the innate immune system in AD
  • Biomarkers in living humans help elucidate the natural history of AD
  • In Vivo APP Labeling
  • Amyloid Imaging and CSF Biomarkers
  • A daunting array of apparent downstream effects in the amyloid cascade
  • Conclusion: mechanistic research offers many avenues toward disease-modifying treatments
  • Acknowledgments
  • References
  • Chapter 2 - The Genetic Basis of Alzheimer's Disease
  • Background
  • Genetics of early-onset familial AD
  • Genetics of late-onset AD
  • Common variants associated with late-onset AD beyond APOE
  • Functional role of the GWAS susceptibility genes in AD
  • Rare variants leading to late-onset AD
  • Summary and future
  • Acknowledgments
  • References
  • Chapter 3 - ß-Secretase Inhibition
  • The role of ß-amyloid in Alzheimer's disease
  • The identification of ß-secretase as ß-site APP cleaving enzyme (BACE)
  • Physiological functions of BACE1
  • BACE1-/- Mice
  • Substrates of BACE1
  • BACE2-/- Mice
  • Small molecule BACE1 inhibitor drugs and clinical trials for AD
  • LY2886721
  • MK-8931
  • AZD3293
  • E2609
  • Alternative Therapeutic Approaches for BACE1 Inhibition
  • Unanswered questions of relevance to BACE1 inhibitor clinical trials
  • What Degree of BACE1 Inhibition Will Be Needed to Achieve Efficacy?
  • At What Stage of AD Should We Administer BACE1 Inhibitors?
  • Will Treatment With BACE1 Inhibitors Cause Mechanism-Based Side Effects?
  • Conclusions
  • Abbreviations
  • Acknowledgments
  • References
  • Chapter 4 - ?-Secretase Inhibitors: From Chemical Probes to Drug Development
  • The ?-secretase complex
  • PS, Nct, Aph1, and Pen2
  • Presenilins
  • Nicastrin
  • Aph1
  • Pen2
  • ?-Secretase inhibitors
  • Active Site-Directed GSIs
  • First-Generation GSIs
  • Clinical GSIs for AD
  • Nonselective GSIs
  • "Notch-Sparing" GSIs
  • PS1 Isoform-Selective GSIs
  • Concluding remarks
  • Acknowledgments
  • References
  • Chapter 5 - Therapeutic Targeting of Aß42
  • Introduction
  • APP processing pathways
  • Targeting Aß42
  • ?-Secretase modulators
  • Clinical development of GSMs
  • Biological approaches to target Aß42
  • Summary and future directions
  • References
  • Chapter 6 - Modulators of Amyloid ß-Protein (Aß) Self-Assembly
  • Introduction
  • Peptidic or peptidomimetic modulators of Aß assembly
  • Aß Fragments or Aß Derivatives
  • CHC-Derived Sequences
  • Conformationally restricted peptides
  • Modified amino acids
  • N-Methylated peptides
  • Cyclic peptides
  • d-Peptides
  • C-Terminal Fragments
  • Peptides and Peptidomimetics From Other Sources
  • Mimicking the Binding Domain of Aß-Binding Proteins
  • Peptides Sharing Common Structural Features With Aß Fragments
  • Rationally Designed Small Peptides
  • De Novo Design
  • Peptide Library Screening
  • Conclusions
  • Aß assembly modulators derived from natural sources
  • Polyphenols
  • Curcumin and Curcumin Derivatives
  • (-)-Epigallocatechin-3-Gallate
  • Flavonoids-Myricetin, Quercetin, Taxifolin, and Fisetin
  • Rosmarinic Acid and Tannic Acid
  • Theaflavins
  • Ginkgo Biloba Extract
  • Brazilin
  • Inositol Derivatives
  • Vitamins
  • Vitamin A
  • Vitamin C
  • Vitamin E
  • Proteins or Peptides
  • Colostrinin
  • Laminin
  • Other Compounds
  • Docosahexaenoic Acid
  • Melatonin
  • Aß assembly modulators from nonnatural sources
  • Small-Molecule Modulators of Aß Assembly and Toxicity
  • Methylene Blue
  • Mitoxantrone, Bithionol, and Hexachlorophene
  • D737
  • Cromolyn Sodium (Disodium Cromoglycate)
  • Aminopyrazole Derivatives
  • Ruthenium Complexes
  • Molecular Tweezers
  • Large Molecules That Modulate Aß Assembly and Toxicity
  • Cucurbit[7]uril
  • Helical Metallocomplexes
  • Polyoxometalates
  • Artificial Molecular Chaperones
  • Conclusions
  • Abbreviations
  • References
  • Chapter 7 - Anti-Amyloid-ß Immunotherapy for Alzheimer's Disease
  • Introduction to Alzheimer's disease
  • AD Genetics
  • AD Pathogenesis
  • AD Biomarkers
  • Current Approved Therapeutics
  • Aß immunotherapy-an introduction
  • Preclinical studies
  • AD-Like Transgenic Mouse Models
  • Active Aß Immunotherapy in Mice
  • DNA-Based Aß Vaccines
  • Passive Aß Immunotherapy in Mice
  • Human clinical trials: active Aß vaccines
  • AN1792
  • Vanutide Cridificar
  • CAD106
  • Affitope AD02
  • ACI-24
  • Human clinical trials: passive Aß immunizations
  • Bapineuzumab
  • Solanezumab
  • Ponezumab
  • GSK933776
  • BAN2401
  • Gantenerumab
  • Crenezumab
  • BIIB037 (Aducanumab)
  • Intravenous Immunoglobulins
  • Summary and conclusions
  • References
  • Internet Resources
  • Chapter 8 - Targeting Aß Receptors to Modify Alzheimer's Disease Progression
  • Introduction
  • General aspects of Aß receptors
  • Which Isoforms of Aß Should a Functional Receptor Bind Selectively?
  • How can we Define a Protein as Receptor for Aßo?
  • How can we Define a Candidate Disease-Relevant Receptor?
  • Potential advantages of targeting an Aßo receptor
  • Cellular prion protein (PrPC) as neuronal cell-surface receptor for Aßo
  • Evidence for PrPC as a Functional Receptor for Aßo
  • Targeting PrPC as Therapeutic Strategy
  • Metabotropic glutamate receptor 5 as coreceptor for Aßo bound to PrPC
  • Evidence for Metabotropic Glutamate Receptor 5 as Coreceptor for Aßo
  • Targeting mGluR5 as Therapeutic Strategy
  • Alternative Coreceptors for Aßo/PrPC Complexes
  • nAchRa7 as receptor for Aß
  • Evidence for nAchRa7 as Receptor for Aß
  • Targeting nAchRa7 as Therapeutic Strategy
  • The interaction between Eph receptors and Aß
  • Evidence for Eph Proteins as Receptors for Aß
  • Targeting Eph Receptors as a Therapeutic Strategy
  • Binding of APP and Aß to Nogo-receptor 1 (NgR1)
  • Evidence for other Aß receptors
  • Mechanisms independent of Aß binding to specific protein receptors
  • Concluding remarks
  • Acknowledgments
  • Disclosure
  • References
  • Chapter 9 - Blood-Brain Barrier Transport of Alzheimer's Amyloid ß-Peptide
  • Introduction
  • Aß clearance from brain
  • LRP1
  • Factors Influencing LRP1-Mediated Aß Clearance
  • Clusterin
  • VLDLR
  • Aß uptake by RAGE
  • Factors Promoting RAGE
  • sRAGE
  • Peripheral sink and systemic clearance of Aß
  • Aß degradation
  • Regulation and restoration of BBB clearance
  • Upregulation of LRP1
  • Upregulation of PICALM
  • sLRP1 Therapy
  • Inhibition of RAGE
  • Downregulation of RAGE
  • Gammagard
  • Young Plasma
  • Conclusions
  • Acknowledgments
  • References
  • Chapter 10 - Alzheimer's Disease Therapeutics Targeting Apolipoprotein E
  • Introduction
  • Physiological function of apoE
  • ApoE and apoE receptors
  • ApoE levels in periphery and CNS
  • ApoE Levels in Plasma
  • ApoE Levels in CSF
  • ApoE Levels in Brain Parenchyma
  • Studies on apoE Metabolism in Mouse Models
  • ApoE and Aß
  • ApoE and Aß Aggregation
  • In Vivo Aggregation Studies in Human Brains and Mouse Models
  • In Vitro Studies on apoE/Aß Binding
  • Effects of apoE on In Vitro Aß Fibrillization
  • ApoE and Aß Clearance
  • ApoE and Enzymatic Degradation of Aß
  • ApoE and BBB Transport of Aß
  • ApoE and Cellular Metabolism of Aß
  • AD therapeutic opportunities targeting apoE
  • Aß Peptides or apoE Fragments That Block Interaction Between apoE and Aß
  • Manipulation of apoE Levels
  • Strategies That Increase apoE Levels
  • Strategies That Decrease apoE Levels
  • ApoE Passive Immunotherapy
  • ApoE Structure Correctors
  • ApoE Lipidation Modification
  • Block apoE Fragmentation
  • ApoE Mimetic Peptides
  • Conclusions
  • References
  • Internet Resource
  • Chapter 11 - Microtubule Stabilization
  • Introduction
  • Microtubules and tau protein
  • Rationale for therapeutic intervention
  • The identification of epothilone D as a potential clinical candidate
  • Other Brain-Penetrant MT-Stabilizing Agents
  • Nonnaturally Occurring MT-Stabilizing Agents
  • Concluding remarks
  • Acknowledgments
  • References
  • Chapter 12 - Tau Phosphorylation as a Therapeutic Target in Alzheimer's Disease
  • Introduction
  • Tau protein structure
  • Tau phosphorylation
  • Tau localization and tau functions
  • Modulation of tau function by phosphorylation
  • Phosphotau toxicity and disease
  • Tau kinase inhibitors
  • References
  • Chapter 13 - Stimulation of Tau Degradation
  • Introduction
  • The ubiquitin proteasome system
  • Overview of the UPS Pathway
  • Evidence of Defects in UPS in AD
  • Tau Processing by the UPS and Pathological Alterations in AD
  • Heat-Shock Proteins and Their Roles in the UPS
  • Treatment Strategies to Increase UPS-Dependent Tau Clearance
  • The autophagy and lysosome pathway
  • Overview of the ALP
  • Evidence of Defects in ALP in AD
  • Tau Processing by the ALP and Dysfunction in AD
  • Treatment Strategies That Increase ALP-Dependent Tau Clearance
  • Cooperation between UPS and ALP in clearing tau
  • Acknowledgments
  • References
  • Chapter 14 - Passive Immunotherapy for Tau Pathology
  • Introduction
  • Spread of tau pathology in the human brain
  • Spread of tau pathology in the rodent brain
  • Tau concentrations and antibody concentrations in the CNS
  • Do antibodies act within neurons?
  • Blocking neuronal tau uptake
  • Microglial uptake
  • Tau export from brain
  • Are existing mouse models appropriate for testing immunotherapy?
  • Problems for active immunization strategies
  • Acknowledgments
  • References
  • Chapter 15 - Inhibition of Tau Aggregation as a Basis for Treatment and Prevention of Alzheimer's Disease
  • Introduction: challenging common preconceptions underlying the rationale in strategies for prevention and treatment of AD p...
  • Sequence of changes in CEREBROSPINAL FLUID amyloid-ß and tau biomarkers
  • Neuropathological sequence of changes in amyloid-ß and tau markers in the neocortex
  • Relationship between tau pathology and cognitive impairment and imaging deficits
  • Temporal sequencing of tau aggregation, pathology, and cognitive impairment
  • The epidemiology of tau aggregation pathology
  • Molecular dissection of the neurofibrillary tangle
  • Modeling tau aggregation in cells
  • Modeling tau aggregation in transgenic animals
  • Identification and optimization of tau aggregation inhibitors for treatment and prevention of AD
  • Activity of TAIs in tau-transgenic mouse models
  • Potential clinical efficacy of TAI therapy in mild or moderate AD
  • Conclusions: prion-like processing of tau protein and its implications for drug development
  • References
  • Chapter 16 - Neuroprotective Strategies for Alzheimer's Disease Prevention and Therapy
  • Roles for neuroprotective strategies
  • Neurotrophin receptors and their signaling pathways
  • p75NTR receptors in AD
  • Trk receptors in AD
  • Neurotrophin-based AD therapies
  • p75NTR-based AD therapeutic strategies
  • TrkA-based AD therapeutic strategies
  • TrkB-based AD therapeutic strategies
  • Conclusions
  • References
  • Chapter 17 - Symptomatic Cognitive Enhancing Agents
  • Definition of "symptomatic" treatment
  • Advantages of symptomatic drug development
  • Targets for symptomatic cognitive enhancing agents
  • Approved Symptomatic Therapies
  • Symptomatic Treatments in Phase 3 Trials
  • Symptomatic Treatments in Early Clinical Development
  • Metabolic Agents
  • Psychotropic Agents With Cognitive Enhancing Properties
  • Synaptic Support Interventions
  • Combination Therapies
  • Devices
  • Outcomes for clinical trials of cognitive enhancing agents
  • Clinical trial designs for cognitive enhancing agents
  • Biomarkers in cognitive enhancing agent drug development
  • Regulatory aspects of cognitive enhancing drug development programs
  • Cognitive enhancing drug development programs
  • Stages of Alzheimer's Disease
  • Non-Alzheimer Indications for Symptomatic Alzheimer Therapies
  • Alternate Formulations
  • Comment and summary
  • Disclosures
  • References
  • Chapter 18 - Tackling Alzheimer's Disease by Targeting Oxidative Stress and Mitochondria
  • Introduction
  • Oxidative biology
  • Sources of Free Radicals
  • Antioxidant Defense
  • Oxidative Damage
  • Oxidative stress in Alzheimer's disease
  • Mitochondrial dysfunction in Alzheimer's disease
  • Oxidative stress and mitochondria as feasible therapeutic targets in Alzheimer's disease
  • Natural Antioxidants
  • Mitochondria-Targeted Antioxidants
  • Modulators of Mitochondrial Function and Dynamics
  • Nonpharmacological Approaches
  • Conclusions
  • References
  • Chapter 19 - Clinical Issues in Alzheimer Drug Development
  • Introduction
  • Clinical issues in drug development
  • Basic Regulatory Requirements for Alzheimer's Drugs
  • Mild Cognitive Impairment Trials
  • Regulatory Considerations for MCI Clinical Trials
  • The Amyloid Cascade Hypothesis
  • Trials in Mild-to-Moderate Alzheimer's Disease Intended to Demonstrate Disease Modification
  • Prodromal Alzheimer's Disease Trials
  • Prevention Trials
  • Diagnoses for regulatory trials in Alzheimer's disease
  • Biomarkers in Alzheimer trials
  • Recent regulatory considerations for drug development in Alzheimer's disease
  • Disease-Modification Claims
  • Discussion and future directions
  • Acknowledgments
  • References
  • Chapter 20 - Molecular Imaging in Alzheimer Clinical Trials
  • Introduction
  • Why PET?
  • PET ligands for amyloid imaging
  • Amyloid PET image analysis
  • Quantitative amyloid PET for diagnostic classification
  • Evaluation of treatment effect
  • Tau PET
  • FDG PET
  • FDG PET in Probable Alzheimer's Dementia
  • FDG PET Prior to Dementia
  • Disease Differentiation
  • Clinical Trajectory Prediction and Stratification
  • Evaluation of Treatment Effect
  • Data Acquisition Considerations
  • Alternative Modalities to FDG
  • Preclinical imaging
  • Amyloid Imaging in Transgenic Mouse Models
  • FDG Imaging in Transgenic Mouse Models
  • Future directions
  • References
  • Chapter 21 - Fluid Biomarkers and Diagnostics
  • Introduction
  • Biomarker concept
  • CSF in Alzheimer's disease
  • CSF Aß42
  • CSF T-tau
  • CSF P-tau
  • Diagnostic Performance of Combined CSF T-tau, P-tau, and Aß42 Tests
  • Longitudinal Changes in CSF AD Biomarkers in Observational and Intervention Studies
  • Candidate AD biomarkers and markers of other pathologies
  • CSF BACE1
  • CSF sAPPa/sAPPß
  • Aß Oligomers
  • Blood-Brain Barrier Biomarkers
  • Additional Biomarkers for Neurodegeneration
  • Biomarkers for Inflammation, Oxidative Stress, and Microglial Activation
  • Biomarkers for Synaptic Changes
  • Other Protein Inclusions
  • AD Biomarkers in Blood
  • CSF biomarkers in relation to the latest clinical trials
  • Standardization efforts
  • Concluding remarks
  • Acknowledgments
  • References
  • Chapter 22 - Nonpharmacologic Activity Interventions to Prevent Alzheimer's Disease
  • Overview
  • Cognitive training
  • Physical exercise and activity
  • Neurobiological targets of benefit: the prefrontal cortex and hippocampus
  • Effects of physical activity on age-related neurobiological targets
  • Lifestyle activity, environmental enrichment, and neurocognitive health
  • Addressing the challenges of sustaining physical activity in later life
  • Yoga and mindfulness activities
  • Increasing cognitive and physical activity in later life through social engagement: multimodal interventions
  • Measuring activity in daily life and at night
  • Conclusions
  • References
  • Chapter 23 - Prospects and Challenges for Alzheimer Therapeutics
  • Introduction
  • Advances in AD pathogenesis and progression
  • Therapeutic targets
  • Clinical trial results: what have we learned?
  • Current pipeline
  • Aß Vaccines
  • Anti-Aß Antibodies
  • ?-Secretase Inhibitors and Modulators
  • ß-Secretase Inhibitors
  • Targeting Tau
  • Repurposing
  • Symptomatic Treatments
  • Key unanswered questions in AD biology
  • Enabling technologies and approaches
  • Summary and conclusions
  • References
  • Index
  • Back cover

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