Developing Therapeutics for Alzheimer's Disease

Progress and Challenges

Michael S. Wolfe

• Publisher: Academic Press
• Year: 2016
• ISBN:
  9780128021644
• Topic: Medicine
• Subtopic: Neurology

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

Chapter 1

The Complex Pathways to Mechanism-Based Therapeutics in Alzheimer’s Disease

D.J. Selkoe

Abstract

A remarkable rise in life expectancy during the last century has made Alzheimer’s disease (AD) the most common form of cognitive decline. AD patients lose their most human qualities—memory, reasoning, abstraction, and language. Biochemical analyses of the classical brain lesions that Alzheimer described in 1906, amyloid plaques and neurofibrillary tangles, preceded and have guided the search for genetic alterations that predispose to AD. A salient example is the recognition that dominantly inherited forms of AD arise from mutations in either the substrate (amyloid β-protein precursor, APP) or the protease (presenilin) of the enzymatic reaction that generates amyloid β-protein (Aβ). Inheritance of the apolipoprotein ɛ4 allele also elevates Aβ levels, principally by interfering with its clearance. Small, soluble oligomers of Aβ impair synaptic form and function, whereas insoluble amyloid plaques sequester these bioactive species and may serve a temporary protective role. The elucidation of genotype-to-phenotype conversions in familial AD, coupled with myriad cell culture and animal model studies of the process, has led to the emergence of specific pharmacological strategies to chronically lower Aβ levels to treat and perhaps prevent AD. Non-Aβ-directed treatments are also moving forward. The varied therapeutic approaches described in this book derive from the success of reductionist biology applied to a disease of the most complex of biological systems, the human brain.

Keywords

protein chemistry

neurodegeneration

Alzheimer’s disease

etiology

pathogenesis

amyloid β-protein

tau protein

genetic factors

microglia

therapeutics

Outline

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 Aβ 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

References

Introduction

Few diagnoses in modern medicine evoke greater apprehension and sadness than Alzheimer’s disease (AD). Virtually unknown to the public just a generation ago, this protean disorder is now the subject of enormous concern on a personal level and represents a looming catastrophe for society. Most people have encountered victims of the disease, not infrequently within their own families, and there is a palpable sense of urgency that something be done. Yet patients told that they have AD quickly learn that no proven disease-modifying treatment exists and that they are destined to experience the insidious loss of their most human qualities—memory, reasoning, abstraction, language, and emotional stability.

Now, based on the power of reductionist biology, this bleak situation appears poised to change. Breathtaking advances in our fundamental knowledge of molecular biology and cellular function during the past half century have provided a platform on which thousands of scientists worldwide are building an understanding of how AD works. Like other new scientific subjects, research on AD has experienced its share of controversy and confusion. But there are far more advances t...

Table of contents

• Cover
• Title page
• Table of Contents
• Copyright
• Dedication
• 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: β-Secretase Inhibition
• Chapter 4: γ-Secretase Inhibitors: From Chemical Probes to Drug Development
• Chapter 5: Therapeutic Targeting of Aβ42
• Chapter 6: Modulators of Amyloid β-Protein (Aβ) Self-Assembly
• Chapter 7: Anti-Amyloid-β Immunotherapy for Alzheimer’s Disease
• Chapter 8: Targeting Aβ Receptors to Modify Alzheimer’s Disease Progression
• Chapter 9: Blood–Brain Barrier Transport of Alzheimer’s Amyloid β-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