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
E-Book | PDF mit Adobe DRM | Systemvoraussetzungen
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
  • Chapter 2 - The Genetic Basis of Alzheimer's Disease
  • Chapter 3 - ß-Secretase Inhibition
  • Chapter 4 - ?-Secretase Inhibitors: From Chemical Probes to Drug Development
  • Chapter 5 - Therapeutic Targeting of Aß42
  • Chapter 6 - Modulators of Amyloid ß-Protein (Aß) Self-Assembly
  • Chapter 7 - Anti-Amyloid-ß Immunotherapy for Alzheimer's Disease
  • Chapter 8 - Targeting Aß Receptors to Modify Alzheimer's Disease Progression
  • Chapter 9 - Blood-Brain Barrier Transport of Alzheimer's Amyloid ß-Peptide
  • Chapter 10 - Alzheimer's Disease Therapeutics Targeting Apolipoprotein E
  • Chapter 11 - Microtubule Stabilization
  • Chapter 12 - Tau Phosphorylation as a Therapeutic Target in Alzheimer's Disease
  • Chapter 13 - Stimulation of Tau Degradation
  • Chapter 14 - Passive Immunotherapy for Tau Pathology
  • Chapter 15 - Inhibition of Tau Aggregation as a Basis for Treatment and Prevention of Alzheimer's Disease
  • Chapter 16 - Neuroprotective Strategies for Alzheimer's Disease Prevention and Therapy
  • Chapter 17 - Symptomatic Cognitive Enhancing Agents
  • Chapter 18 - Tackling Alzheimer's Disease by Targeting Oxidative Stress and Mitochondria
  • Chapter 19 - Clinical Issues in Alzheimer Drug Development
  • Chapter 20 - Molecular Imaging in Alzheimer Clinical Trials
  • Chapter 21 - Fluid Biomarkers and Diagnostics
  • Chapter 22 - Nonpharmacologic Activity Interventions to Prevent Alzheimer's Disease
  • Chapter 23 - Prospects and Challenges for Alzheimer Therapeutics
  • Index
  • Back cover
  • Future directions
  • References
  • Introduction
  • Advances in AD pathogenesis and progression
  • Therapeutic targets
  • Clinical trial results: what have we learned?
  • Current pipeline
  • CSF biomarkers in relation to the latest clinical trials
  • Standardization efforts
  • Acknowledgments
  • References
  • Key unanswered questions in AD biology
  • Enabling technologies and approaches
  • Summary and conclusions
  • References
  • Overview
  • Cognitive training
  • Physical exercise and activity
  • 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
  • Increasing cognitive and physical activity in later life through social engagement: multimodal interventions
  • Measuring activity in daily life and at night
  • Conclusions
  • References
  • Introduction
  • Biomarker concept
  • Candidate AD biomarkers and markers of other pathologies
  • 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
  • Diagnoses for regulatory trials in Alzheimer's disease
  • Biomarkers in Alzheimer trials
  • Recent regulatory considerations for drug development in Alzheimer's disease
  • Discussion and future directions
  • Acknowledgments
  • References
  • Preclinical imaging
  • Introduction
  • Clinical issues in drug development
  • Oxidative stress in Alzheimer's disease
  • Mitochondrial dysfunction in Alzheimer's disease
  • Oxidative stress and mitochondria as feasible therapeutic targets in Alzheimer's disease
  • Conclusions
  • References
  • Introduction
  • Oxidative biology
  • Cooperation between UPS and ALP in clearing tau
  • Acknowledgments
  • References
  • Comment and summary
  • References
  • The autophagy and lysosome pathway
  • Outcomes for clinical trials of cognitive enhancing agents
  • Biomarkers in cognitive enhancing agent drug development
  • Regulatory aspects of cognitive enhancing drug development programs
  • Definition of "symptomatic" treatment
  • Advantages of symptomatic drug development
  • Targets for symptomatic cognitive enhancing agents
  • 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
  • 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
  • Introduction
  • Spread of tau pathology in the human brain
  • Tau concentrations and antibody concentrations in the CNS
  • Do antibodies act within neurons?
  • Microglial uptake
  • Tau export from brain
  • Problems for active immunization strategies
  • Acknowledgments
  • References
  • Introduction
  • The ubiquitin proteasome system
  • Conclusions
  • References
  • Internet Resource
  • Concluding remarks
  • Acknowledgments
  • References
  • 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
  • Introduction
  • Microtubules and tau protein
  • Rationale for therapeutic intervention
  • The identification of epothilone D as a potential clinical candidate
  • Conclusions
  • References
  • AD therapeutic opportunities targeting apoE
  • Introduction
  • Physiological function of apoE
  • ApoE and apoE receptors
  • ApoE levels in periphery and CNS
  • Peripheral sink and systemic clearance of Aß
  • Regulation and restoration of BBB clearance
  • ApoE and Aß
  • Introduction
  • Aß clearance from brain
  • Aß uptake by RAGE
  • nAchRa7 as receptor for Aß
  • The interaction between Eph receptors and Aß
  • Binding of APP and Aß to Nogo-receptor 1 (NgR1)
  • Evidence for other Aß receptors
  • Concluding remarks
  • References
  • Introduction
  • Conclusions
  • Abbreviations
  • References
  • Summary and conclusions
  • References
  • Internet Resources
  • Potential advantages of targeting an Aßo receptor
  • Cellular prion protein (PrPC) as neuronal cell-surface receptor for Aßo
  • Metabotropic glutamate receptor 5 as coreceptor for Aßo bound to PrPC
  • Introduction to Alzheimer's disease
  • Aß immunotherapy-an introduction
  • Preclinical studies
  • Human clinical trials: active Aß vaccines
  • Human clinical trials: passive Aß immunizations
  • Aß assembly modulators derived from natural sources
  • Aß assembly modulators from nonnatural sources
  • Introduction
  • Peptidic or peptidomimetic modulators of Aß assembly
  • ?-Secretase inhibitors
  • Clinical GSIs for AD
  • Concluding remarks
  • Acknowledgments
  • References
  • Introduction
  • APP processing pathways
  • Targeting Aß42
  • ?-Secretase modulators
  • Clinical development of GSMs
  • Biological approaches to target Aß42
  • Summary and future directions
  • References
  • The ?-secretase complex
  • PS, Nct, Aph1, and Pen2
  • A daunting array of apparent downstream effects in the amyloid cascade
  • References
  • Conclusions
  • Abbreviations
  • References
  • 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
  • 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
  • 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
  • Small molecule BACE1 inhibitor drugs and clinical trials for AD
  • Unanswered questions of relevance to BACE1 inhibitor clinical trials
  • 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
  • Summary and future
  • Acknowledgments
  • References
  • Introduction
  • 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
  • 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?
  • LY2886721
  • MK-8931
  • AZD3293
  • Alternative Therapeutic Approaches for BACE1 Inhibition
  • In Vivo APP Labeling
  • BACE1-/- Mice
  • Substrates of BACE1
  • BACE2-/- Mice
  • Presenilins
  • Nicastrin
  • Pen2
  • Nonselective GSIs
  • "Notch-Sparing" GSIs
  • PS1 Isoform-Selective GSIs
  • Aß Fragments or Aß Derivatives
  • Small-Molecule Modulators of Aß Assembly and Toxicity
  • Proteins or Peptides
  • Other Compounds
  • Large Molecules That Modulate Aß Assembly and Toxicity
  • Polyphenols
  • Peptides and Peptidomimetics From Other Sources
  • Inositol Derivatives
  • Vitamins
  • Bapineuzumab
  • Solanezumab
  • GSK933776
  • Crenezumab
  • Intravenous Immunoglobulins
  • AN1792
  • Vanutide Cridificar
  • CAD106
  • AD-Like Transgenic Mouse Models
  • Active Aß Immunotherapy in Mice
  • Passive Aß Immunotherapy in Mice
  • AD Genetics
  • AD Biomarkers
  • Current Approved Therapeutics
  • Evidence for Metabotropic Glutamate Receptor 5 as Coreceptor for Aßo
  • Targeting mGluR5 as Therapeutic Strategy
  • Alternative Coreceptors for Aßo/PrPC Complexes
  • Evidence for PrPC as a Functional Receptor for Aßo
  • Targeting PrPC as Therapeutic Strategy
  • Which Isoforms of Aß Should a Functional Receptor Bind Selectively?
  • How can we Define a Protein as Receptor for Aßo?
  • Evidence for Eph Proteins as Receptors for Aß
  • Targeting Eph Receptors as a Therapeutic Strategy
  • Targeting nAchRa7 as Therapeutic Strategy
  • Factors Promoting RAGE
  • Conclusions
  • Clusterin
  • LRP1
  • ApoE and Aß Aggregation
  • Upregulation of LRP1
  • Inhibition of RAGE
  • Young Plasma
  • ApoE Levels in Plasma
  • ApoE Levels in CSF
  • Studies on apoE Metabolism in Mouse Models
  • Aß Peptides or apoE Fragments That Block Interaction Between apoE and Aß
  • ApoE and Aß Clearance
  • Other Brain-Penetrant MT-Stabilizing Agents
  • Nonnaturally Occurring MT-Stabilizing Agents
  • ApoE Passive Immunotherapy
  • ApoE Structure Correctors
  • ApoE Lipidation Modification
  • Block apoE Fragmentation
  • Overview of the UPS Pathway
  • Evidence of Defects in UPS in AD
  • Approved Symptomatic Therapies
  • Symptomatic Treatments in Phase 3 Trials
  • Metabolic Agents
  • Psychotropic Agents With Cognitive Enhancing Properties
  • Stages of Alzheimer's Disease
  • Non-Alzheimer Indications for Symptomatic Alzheimer Therapies
  • 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
  • Sources of Free Radicals
  • Antioxidant Defense
  • Treatment Strategies to Increase UPS-Dependent Tau Clearance
  • Nonpharmacological Approaches
  • Natural Antioxidants
  • Mitochondria-Targeted Antioxidants
  • Basic Regulatory Requirements for Alzheimer's Drugs
  • Mild Cognitive Impairment 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
  • Amyloid Imaging in Transgenic Mouse Models
  • FDG Imaging in Transgenic Mouse Models
  • Disease-Modification Claims
  • FDG PET in Probable Alzheimer's Dementia
  • Disease Differentiation
  • Clinical Trajectory Prediction and Stratification
  • Data Acquisition Considerations
  • Alternative Modalities to FDG
  • CSF BACE1
  • CSF sAPPa/sAPPß
  • Blood-Brain Barrier Biomarkers
  • Biomarkers for Inflammation, Oxidative Stress, and Microglial Activation
  • Biomarkers for Synaptic Changes
  • Other Protein Inclusions
  • CSF Aß42
  • CSF T-tau
  • CSF P-tau
  • Aß Vaccines
  • Anti-Aß Antibodies
  • ?-Secretase Inhibitors and Modulators
  • ß-Secretase Inhibitors
  • Targeting Tau
  • Symptomatic Treatments
  • Regulatory Considerations for MCI Clinical Trials
  • Modulators of Mitochondrial Function and Dynamics
  • Tau Processing by the UPS and Pathological Alterations in AD
  • Heat-Shock Proteins and Their Roles in the UPS
  • ApoE and Enzymatic Degradation of Aß
  • ApoE and Cellular Metabolism of Aß
  • Strategies That Increase apoE Levels
  • Strategies That Decrease apoE Levels
  • In Vivo Aggregation Studies in Human Brains and Mouse Models
  • In Vitro Studies on apoE/Aß Binding
  • Factors Influencing LRP1-Mediated Aß Clearance
  • Vitamin A
  • Vitamin C
  • Vitamin E
  • Mimicking the Binding Domain of Aß-Binding Proteins
  • Rationally Designed Small Peptides
  • Peptide Library Screening
  • Curcumin and Curcumin Derivatives
  • (-)-Epigallocatechin-3-Gallate
  • Flavonoids-Myricetin, Quercetin, Taxifolin, and Fisetin
  • Rosmarinic Acid and Tannic Acid
  • Theaflavins
  • Ginkgo Biloba Extract
  • Brazilin
  • Cucurbit[7]uril
  • Helical Metallocomplexes
  • Polyoxometalates
  • Artificial Molecular Chaperones
  • Docosahexaenoic Acid
  • Melatonin
  • Colostrinin
  • Methylene Blue
  • Mitoxantrone, Bithionol, and Hexachlorophene
  • D737
  • Cromolyn Sodium (Disodium Cromoglycate)
  • Aminopyrazole Derivatives
  • Ruthenium Complexes
  • Molecular Tweezers
  • CHC-Derived Sequences
  • C-Terminal Fragments
  • d-Peptides
  • Conformationally restricted peptides
  • Modified amino acids
  • N-Methylated peptides
  • Cyclic peptides

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