Pharmacological Mechanisms in Alzheimer's Therapeutics (eBook)

Forewords 5
Preface from the Editor 8
Contents 10
List of Contributors 13
Overview of the AlzheimerÌs Disease Pathology and Potential Therapeutic Targets 19
Introduction 19
Alois AlzheimerÌs Realization of a Dementia Accompanied with a Defined Brain Pathology 19
Key Molecules in the AlzheimerÌs Pathology 21
The Amyloid Hypothesis 22
Tau Pathology in AlzheimerÌs 24
Additional Components of the AlzheimerÌs Pathology 25
Clinical Evolution and Diagnosis of AlzheimerÌs Disease, a Synopsis 27
Genetic and Nongenetic Risk Factors in AD 28
Nongenetic Risk Factors 29
Aging as a Risk Factor 29
High Plasma Cholesterol 30
Hypertension 30
Oxidative Stress as a Risk Factor 31
Education, Physical Activity, and Brain Trauma and the Onset of AlzheimerÌs 31
Synapses, Neurotransmitters, and Growth Factors in the AlzheimerÌs Pathology 32
Present and Future Pharmacological Treatment of AlzheimerÌs Disease 34
Concluding Remarks 38
References 38
Trial Designs and Outcomes to Monitor Novel Therapeutics in Alzheimer's Disease 46
Introduction 46
Symptomatic Treatment Versus Disease Stabilization 46
Natural History of AlzheimerÌs Disease 47
Symptomatic Clinical Trials Using ChEI and Memantine 49
Disease-Modification Studies 50
Conclusions 51
References 51
The Pharmacological Treatment of AlzheimerÌs Disease with Cholinesterase Inhibitors and Memantine 54
Introduction 54
Cholinesterase Inhibitors Tacrine 54
Second Generation Cholinesterase Inhibitors for Mild- to- Moderate AD 55
Cholinesterase Inhibitors in Severe AD 57
Cholinesterase Inhibitors for the Management of Noncognitive Symptoms in Dementia 58
Long-Term Use of Cholinesterase Inhibitors 58
Use of Cholinesterase inhibitors in Other Conditions 60
Memantine for the Treatment of Dementia Introduction 62
Memantine for the Treatment of AlzheimerÌs Disease 62
Memantine for the Treatment of Vascular Dementia 63
Memantine Combined with a Cholinesterase Inhibitor 63
Conclusions 64
References 64
M1 Muscarinic Agonists: A Comprehensive Therapy Against Major Hallmarks of Alzheimer's Disease 68
Introduction 68
M1 Muscarinic Agonists in AD Ò the Rationale 69
Past Experience and Present Status 69
Modulation of Ab Levels via M1 mAChR 70
M1 mAChR Mediate Dephosphorylation of Tau Proteins 73
Prevention of Ab Neurotoxic Effects Wnt Signaling
Relevant Clinical Data on Disease Modification 74
Conclusions and Outlook 74
References 76
Cholinergic Neurodegeneration in Alzheimer's Disease: 82
Introduction 82
Basal Forebrain Cholinergic Neurons Anatomy 84
Cholinergic Biochemistry and Cellular Physiology 84
Network Physiology and Function 86
Lesions and Cognition 88
AlzheimerÌs Disease 89
Animal Models of AlzheimerÌs Disease 91
Cholinergic Neurotransmission and APP Metabolism 92
Role of Neurotrophins in the Maintenance of BFCNs Structure and Function 93
Failed NGF Signaling in AlzheimerÌs Disease 94
NGF Signaling in Mouse Models of Alzheimer Overexpressing Mutant APP 95
Mouse Models of AlzheimerÌs Disease Overexpressing Wild- Type Human APP 97
Mouse Models of Down Syndrome 98
Mechanisms by Which NGF Transport is Interrupted in Degenerating Cholinergic Neurons 102
Therapeutic Strategies for AlzheimerÌs Disease Focused on Enhancing NGF Signaling 104
Direct NGF Administration 104
Enhancing NGF Downstream Signaling 105
Increasing NGF Retrograde Transport 107
Conclusions 108
References 109
The Rationale for Glutamatergic Therapy in Alzheimer's Disease 123
Glutamatergic Neurotransmission 123
Markers of Glutamate Neurotransmission in AlzheimerÌs Disease 124
The Glutamatergic System and AD Pathology 125
Glutamatergic System in Transgenic Models of AD 126
Glutamatergic Approaches to Treatment of AD 126
Conclusions 127
References 127
Secretases as Pharmacological Targets in Alzheimer's Disease 131
Introduction 131
Inhibition of ß- Secretase 133
Inhibition of .- Secretase 135
Activation of a- Secretase 135
Conclusions 136
References 137
y-Secretase as a Target forAlzheimerÌs Disease 143
.- Secretase and Production of Amyloid ß- Peptide 143
Identification of the .- Secretase Complex 144
Mechanism of .- Secretase and Role in Notch Signaling 146
Therapeutic Potential of .- Secretase Inhibitors 148
Therapeutic Potential of .- Secretase Modulators 150
Conclusions 153
References 153
The Rationale for an Immunological Approach to Alzheimer's Therapeutics 159
References 164
Neuroinflammation, Alzheimer Disease, and Other Aging Disorders 167
Introduction 167
Microglia 168
Mitosis 169
Chemotaxis 169
Phagocytosis 171
Complement 172
Neurotoxicity 172
Healing 174
Possible Use of Antiinflammatory Agents in Treating Alzheimer Disease 174
Inflammation as an Important Factor in Many Aging Diseases 176
References 177
Nonsteroidal Anti-inflammatory Drugs ( NSAIDs) and Derived A 42- Lowering Molecules for Treatment and Prevention of AlzheimerÌs Disease ( AD) 185
Prevalence, Neuropathology, and Etiology of AlzheimerÌs Disease 186
NSAIDs and AD: The Epidemiological Evidence and Overview of Potential Mechanisms of Action 187
Role of Inflammation in AD 188
Protective Mechanisms Related to the Anti-inflammatory Properties of NSAIDs 191
A 42 as a Therapeutic Target in AlzheimerÌs Disease 194
Selective Modulation of A 42 Production with NSAIDs 195
Clinical Trials with NSAIDs and Derived A 42- Lowering Compounds 199
Conclusion 202
References 203
The Potential Application of Antioxidant Agents in Alzheimer Disease Therapeutics 212
Introduction 212
Main Sources of Oxidative Stress in AD Mitochondria 213
Redox-Active Metals 215
Could Antioxidant Agents Prevent the Deleterious Consequences of Oxidative Stress? 217
Direct Antioxidants 217
Metabolic Antioxidants 219
Indirect Antioxidants 221
Conclusions 223
References 224
Apolipoprotein E: A Potent Gene- Based Therapeutic Target for the Treatment of Sporadic AlzheimerÌs Disease 230
Introduction 230
Apolipoprotein E: A Sound Therapeutic Target 232
Conclusion 237
References 238
Tau Pathology as a Target in AlzheimerÌs Therapeutics 241
Introduction 241
Mechanism of Neurofibrillary Degeneration 242
Therapeutic Approaches 244
References 248
Design of Inhibitors of Amyloid- ß Misfolding and Aggregation for Alzheimer's Therapy 256
Introduction 256
Amyloid- ß Misfolding and Aggregation is a Key Event in AD 256
Amyloid- ß Toxicity Requires a ß- Sheet Rich Conformation 258
Strategies to Inhibit A Misfolding and Aggregation 259
The ß- Sheet- Breaker Strategy 262
Use of Nanotechnology to Produce Amyloid Inhibitors 264
Concluding Remarks 266
References 266
Potential Applications of Glycosaminoglycan-Related Compounds in AlzheimerÌs Disease 273
Introduction 273
Relevance of Proteoglycans in AD Pathology Proteoglycans ( PGs) 274
Association of PGs with AlzheimerÌs Disease Pathophysiology 275
Association of PGs with Cerebral Amyloid Angiopathy 276
Interaction of PGs with APP 277
Interaction of PGs with Ab 278
Protection of GAGs Against Ab- Induced Neurotoxicity 278
Interaction of PGs and GAGs with Tau Protein 279
Potential Application of GAG-Related Compounds in AD 280
Chondroitin Sulfate-derived Monosaccharides and Disaccharides 280
Heparin Derivatives 281
C3, C6, and Certoparin 281
Acidic Oligosaccharide Sugar Chain 282
Ateroid 282
Sulfates and Sulfonates 282
References 284
Multifunctional Neuroprotective Drugs for the Treatment of Alzheimer's Disease 292
Introduction 292
Existing Drugs Discovered or Identified to Possess Two or More Cotargeted Therapeutic Mechanisms of Action 294
Drugs Specifically Designed to Possess Two or More Cotargeted Therapeutic Mechanisms of Action Cholinesterase/ MAO- B Inhibitors with Additional Cotargeted Mechanisms 296
Multifunctional Neuroprotective Iron Chelators with Radical- Scavenging and Brain- Selective Monoamine Oxidase Inhibitory Activity 298
Anti-inflammatory Agents with Antioxidant Activities 300
Adenosine A 302
Antagonists with Concomitant 302
Monoamine 302
Oxidase 302
Inhibitory Activity 302
NMDA Antagonists That Also Act as Calcium Channel Blockers 302
Glutamate Antagonists That Also Act as Glutamate- Release Inhibitors 305
Multiple Ion Channel Modulators 307
Conclusion 307
References 308
Interpreting Clinical Studies of Putative Therapeutics for Alzheimer's Disease: The Case of Statins and NSAIDs 314
Introduction 314
Pharmacological Studies in Humans: A Primer 314
Statins: Can Cholesterol Metabolism Modify the Pathophysiology of AD? 317
Nonsteroidal Anti-inflammatory Drugs 321
Conclusion 322
References 323
Index 327