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Developing Therapeutics for Alzheimer's Disease: Progress and Challenges
Wolfe, Michael S. (Edt)
Academic Press / Hardcover / 2016-06-01 / 012802173X
Dementia / Medicine: Pharmacy
reg price: $276.50 our price: $ 262.68 (may be subject to change)
676 pages
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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.

Table of Contents:

Dedication
List of Contributors
Foreword
Preface
Chapter 1: The Complex Pathways to Mechanism-Based Therapeutics in Alzheimer’s Disease
Abstract
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
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
A daunting array of apparent downstream effects in the amyloid cascade
Conclusion: mechanistic research offers many avenues toward disease-modifying treatments
Acknowledgments
Chapter 2: The Genetic Basis of Alzheimer’s Disease
Abstract
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
Chapter 3: ß-Secretase Inhibition
Abstract
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
Small molecule BACE1 inhibitor drugs and clinical trials for AD
Unanswered questions of relevance to BACE1 inhibitor clinical trials
Conclusions
Abbreviations
Acknowledgments
Chapter 4: ?-Secretase Inhibitors: From Chemical Probes to Drug Development
Abstract
The ?-secretase complex
PS, Nct, Aph1, and Pen2
?-Secretase inhibitors
Active site-directed GSIs
First-Generation GSIs
Clinical GSIs for AD
Concluding remarks
Acknowledgments
Chapter 5: Therapeutic Targeting of Aß42
Abstract
Introduction
APP processing pathways
Targeting Aß42
?-Secretase modulators
Clinical development of GSMs
Biological approaches to target Aß42
Summary and future directions
Chapter 6: Modulators of Amyloid ß-Protein (Aß) Self-Assembly
Abstract
Introduction
Peptidic or peptidomimetic modulators of Aß assembly
Aß assembly modulators derived from natural sources
Aß assembly modulators from nonnatural sources
Conclusions
Abbreviations
Chapter 7: Anti-Amyloid-ß Immunotherapy for Alzheimer’s Disease
Abstract
Introduction to Alzheimer’s disease
Aß immunotherapy—an introduction
Preclinical studies
Human clinical trials: active Aß vaccines
Human clinical trials: passive Aß immunizations
Summary and conclusions
Chapter 8: Targeting Aß Receptors to Modify Alzheimer’s Disease Progression
Abstract
Introduction
General aspects of Aß receptors
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
nAchRa7 as receptor for Aß
The interaction between Eph receptors and Aß
Binding of APP and Aß to Nogo-receptor 1 (Nf08-01-9780128021736)
Evidence for other Aß receptors
Mechanisms independent of Aß binding to specific protein receptors
Concluding remarks
Acknowledgments
Disclosure
Chapter 9: Blood–Brain Barrier Transport of Alzheimer’s Amyloid ß-Peptide
Abstract
Introduction
Aß clearance from brain
Aß uptake by RAGE
Peripheral sink and systemic clearance of Aß
Aß degradation
Regulation and restoration of BBB clearance
Conclusions
Acknowledgments
Chapter 10: Alzheimer’s Disease Therapeutics Targeting Apolipoprotein E
Abstract
Introduction
Physiological function of apoE
ApoE and apoE receptors
ApoE levels in periphery and CNS
ApoE and Aß
AD therapeutic opportunities targeting apoE
Conclusions
Chapter 11: Microtubule Stabilization
Abstract
Introduction
Microtubules and tau protein
Rationale for therapeutic intervention
The identification of epothilone D as a potential clinical candidate
Concluding remarks
Acknowledgments
Chapter 12: Tau Phosphorylation as a Therapeutic Target in Alzheimer’s Disease
Abstract
Introduction
Tau protein structure
Tau phosphorylation
Tau localization and tau functions
Modulation of tau function by phosphorylation
Phosphotau toxicity and disease
Tau kinase inhibitors
Chapter 13: Stimulation of Tau Degradation
Abstract
Introduction
The ubiquitin proteasome system
The autophagy and lysosome pathway
Cooperation between UPS and ALP in clearing tau
Acknowledgments
Chapter 14: Passive Immunotherapy for Tau Pathology
Abstract
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
Chapter 15: Inhibition of Tau Aggregation as a Basis for Treatment and Prevention of Alzheimer’s Disease
Abstract
Introduction: challenging common preconceptions underlying the rationale in strategies for prevention and treatment of AD pathology
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
Chapter 16: Neuroprotective Strategies for Alzheimer’s Disease Prevention and Therapy
Abstract
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
Chapter 17: Symptomatic Cognitive Enhancing Agents
Abstract
Definition of “symptomatic” treatment
Advantages of symptomatic drug development
Targets for symptomatic cognitive enhancing agents
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
Comment and summary
Chapter 18: Tackling Alzheimer’s Disease by Targeting Oxidative Stress and Mitochondria
Abstract
Introduction
Oxidative biology
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
Chapter 19: Clinical Issues in Alzheimer Drug Development
Abstract
Introduction
Clinical issues in drug development
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
Chapter 20: Molecular Imaging in Alzheimer Clinical Trials
Abstract
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
Preclinical imaging
Future directions
Chapter 21: Fluid Biomarkers and Diagnostics
Abstract
Introduction
Biomarker concept
CSF in Alzheimer’s disease
Candidate AD biomarkers and markers of other pathologies
CSF biomarkers in relation to the latest clinical trials
Standardization efforts
Concluding remarks
Acknowledgments
Chapter 22: Nonpharmacologic Activity Interventions to Prevent Alzheimer’s Disease
Abstract
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
Chapter 23: Prospects and Challenges for Alzheimer Therapeutics
Abstract
Introduction
Advances in AD pathogenesis and progression
Therapeutic targets
Clinical trial results: what have we learned?
Current pipeline
Key unanswered questions in AD biology
Enabling technologies and approaches
Summary and conclusions
Index

About the Editor:

Michael S. Wolfe is Professor of Neurology at Harvard Medical School and Brigham and Women’s Hospital. He received his B.S. in chemistry in 1984 from the Philadelphia College of Pharmacy and Science and Ph.D. in medicinal chemistry in 1990 from the University of Kansas. After postdoctoral stints at the University of Kansas (medicinal chemistry) and the NIH (cell biology), he joined the faculty of the University of Tennessee in Memphis in 1994. In 1999, he moved to Harvard Medical School, where his work has focused on understanding the molecular basis of Alzheimer’s Disease and related disorders, and identifying effective approaches for pharmacological intervention. Awards for his work include the Sato Memorial International Award in bioorganic and medicinal chemistry from the Pharmaceutical Society of Japan (2003), the MetLife Award for Biomedical Research (2008), a Zenith Fellows Award from the Alzheimer’s Association (2008), and the Potamkin Prize from the American Academy of Neurology (2009).


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