Advances in Alzheimer's and Parkinson's Disease (eBook)

Preface 6
Contents 7
Contributors 12
Clinical Features and Treatment of Dementia Associated With Parkinson’s Disease 30
Introduction 30
Clinical Features of Dementia Associated With PD 30
Cognitive Features 31
Behavioral Features 32
Treatment of PDD 32
Conclusions 35
References 35
Neurogenetics in Parkinson’s Disease 37
Introduction 37
PARK1 37
PARK2 38
PARK3 39
PARK4 40
PARK5 40
PARK6 40
PARK7 41
PARK8 41
PARK9, PARK10, PARK11 42
Other Forms of Familial PD 43
References 43
Impaired DNA Repair Systems: Generation of Mitochondrial Dysfunction and Increased Sensitivity to Excitotoxicity 45
Introduction 45
Results 46
Conclusions 48
References 48
Current Problems and Strategies in Motor Rehabilitation for Parkinson’s Disease 50
Introduction 50
Clinical Research on Rehabilitation for PD 51
Current Problems in Rehabilitation for PD 52
Neurophysiological Approach to Motor Rehabilitation 52
Possible Limitations of Rehabilitation for PD 54
Conclusions 55
References 55
Critical Acute Akinesia in Parkinson’s Disease Patients Concomitant with Additional Precipitating Factors Other Than Treatment Withdrawal: A Possible Lethal Complication 58
Introduction 58
Conclusion 61
References 61
Biomarkers for Early Detection of Parkinson’s Disease: An Essential Challenge 62
Introduction 62
Current Diagnosis of Parkinson’s Disease 63
Translation of Pathological Findings into Biomarkers 64
From Neurochemical Findingshellip 64
...To Pathological Staging... 65
...Toward Diagnostic Staging... 66
... En Route to Translation into Biomarkers 66
Potential Biomarkers for PD 67
Functional Imaging 67
Transcranial Ultrasonography 67
Tests on Olfaction 68
Tests on Vision 68
Biochemical Markers 68
Neuromelanin Blood Test 69
Genetic Markers 69
Gene Expression in Blood-A Future Diagnostic Tool? 70
Conclusion 70
References 71
Neurotransmitter and Neurotrophic Factor-Secreting Cell Line Grafting for the Treatment of Parkinson’s Disease 77
Introduction 77
Cell Grafting for Parkinson’s Disease 77
Cell Line Grafting and Encapsulation 78
Neurotransmitter-Secreting Cell Line Grafting 78
Neurotrophic Factor-Secreting Cell Line Grafting 79
Simultaneous Delivery of Neurotransmitter and Neurotrophic Factor by Cell Line Grafting 79
Intracerebral Grafting of Human-Derived Cell Line 80
Control of Neurotransmitter and Neurotrophic Factor Secretion After Grafting into the Brain 80
Clinical Reports of Encapsulated Cell or Cell Line Grafting for Neurological Disorders 81
Conclusion 81
References 82
Novel Therapeutic Target in PD: Experimental Models 83
Introduction 83
Ideal Model of Parkinson’s Disease 84
6-Hydroxydopamine 84
MPTP 85
Rotenone 86
New In Vivo Environmental Models of Parkinson’s Disease 88
Subcutaneous Rotenone Exposure 88
Continuous Administration of MPTP 88
Genes Associated with Parkinson’s Disease and Genetic Models 89
Parkin 90
Ubiquitin C-Terminal Hydroxylase-L1 91
DJ-1 91
a-Synuclein 92
Inhibition of the UP System: One Cause of Parkinson’s Disease 93
Novel Therapeutic Target in Parkinson’s Disease 94
References 95
LRRK2 (Leucine-Rich Repeat Kinase 2) Gene on PARK8 Locus in Families with Parkinsonism 100
Introduction 100
Clinical and Pathological Characterization of Families with the LRRK2 Gene 100
Family D (Western Nebraska) 100
Family A (German-Canadian) 104
Family 469 107
PET Studies 107
LRRK2/ROCO Gene 107
Additional LRRK2 Families 108
G2019S Families 108
Basque Families and British Kindred 109
Sagamihara Family 109
Discussion 110
References 113
Microglia Activation and Gene Expression of Cytokines in Parkinson’s Disease 115
Introduction 115
Increased Levels of Cytokines from Activated Microglia in the Putamen in PD 116
Increased Activated Microglia Associated With Damaged Dopamine Neurons During the Progression of PD 116
Activated Microglia in the Substantia Nigra, Putamen, and Various Regions of the Brain in PD 116
Different Expression of Cytokines in the Hippocampus and Putamen in PD and LBD 117
Neuroprotective and Neurotoxic Subtypes of Activated Microglia in the PD Brain 118
Conclusion 118
References 119
Dissecting the Biochemical Pathways Mediated by Genes Implicated in Parkinson’s Disease: Induction of DJ-1 Expression in A30P balpha-Synuclein Mice 120
Introduction 120
Materials and Methods 122
Animals 122
Antibodies and Immunohistochemistry 122
Brain Tissue Extraction 123
Immunoblot Analysis 123
Quantification of Immunoblots 123
Carbonyl Detection 124
Immunoprecipitation 124
DJ-1 siRNA Transfection 124
LDH assay 125
Results 125
Symptomatic Mice Exhibit Elevated DJ-1 Levels 125
Symptomatic Mice Have Increased Oxidation 126
DJ-1 Is Present in Reactive Astrocytes in Brain Sections from the Contursi Kindred 126
DJ-1 Co-immunoprecipitates with Tau and Phospho-tau in Brain Homogenates 128
DJ-1 siRNA Knockdown Confers Susceptibility to Oxidative Insult in Cell Culture 129
Discussion 130
References 132
Neuroinflammation in Early Stages of Alzheimer’s Disease and Parkinson’s Disease 136
Introduction 136
AB Deposition and the Neuroinflammatory Response in AD 137
Neuroinflammation and Regenerative Pathways in AD 138
Inflammation and the Pathological Cascade in AD 139
Inflammation and the Pathological Cascade in PD 140
Conclusions 141
References 142
Alzheimer’s Disease, Parkinson’s Disease, and Frontotemporal Dementias: Different Manifestations of Protein Misfolding 145
IntroductionDue to the explosive growth in new information on the genetic and molecular pathology of the neurodegenerative diseases discussed here, which have been the subject of numerous reviews from many diverse perspectives, only a limited number of recent primary publications are listed and additional earlier literature citations are available in the recent reviews cited here. 145
Alzheimer’s Disease and Related Tauopathies 146
Parkinson’s Disease, Related Synucleinopathies, and Other Parkinsonian Movement Disorders 148
Conclusions 151
References 151
Role of Oxidative Insult and Neuronal Survival in Alzheimer’s and Parkinson’s Diseases 154
Introduction 154
Neuronal Death in AD and PD 154
Oxidative Insults and Cell Cycle Reentry at an Early Stage of Neurodegeneration 156
Association of Oxidative Stress with Genetic Mutations and Risk Factors for AD and PD 156
Primary Role of Oxidative Stress in AD and PD 157
Cell Cycle Reentry in AD and PD 159
Pathological Hallmarks and Neuronal Survival Response 160
Pathological Hallmarks: Pathogenic, Incidental, or a Beneficial Coping Response? 160
Possible Protective Function of Abeta, Tau, and Alpha-Synuclein Against Oxidative Stress 161
Conclusions 163
References 163
Redox Proteomics Identification of Oxidatively Modified Proteins in Alzheimer’s Disease Brain and in Brain from a Rodent Model of Familial Parkinson’s Disease: Insights into Potential Mechanisms of Neurodegeneration 170
Introduction 170
Proteomics 171
Alzheimer’s Disease 175
Energy Dysfunction 177
Excitotoxicity 178
Proteasomal Dysfunction 178
Lipid Abnormalities and Cholinergic Dysfunction 178
Neuritic Abnormalities 179
Tau Hyperphosphorylation 179
Synaptic Abnormalities and LTP 179
pH Buffering and CO2 Transport 180
AD Models for Abeta(1-42) 180
Parkinson’s Disease 180
Redox Proteomics in PD 181
Conclusions 182
References 183
Biomarkers for Alzheimer’s Disease and Parkinson’s Disease 189
Introduction 189
Definitions 190
Amyloid Fragments and Tau in AD 191
Biomarkers in Body Fluids of PD Patients 193
References 194
Bioluminescent Imaging of Excitotoxic and Endotoxic Brain Injury in Living Mice 195
Introduction 195
Methods 196
Mice and Injury Models 196
Stereotactic Injections 196
Tissue Preparation 197
Bioluminescence Imaging 197
Results and Discussion 197
SBE-luc Reporter Mice 197
Bioluminescent Imaging of Excitotoxic Brain Injury 199
Noninvasive Imaging of Endotoxic Brain Injury In Vivo 199
References 202
Alzheimer’s Disease Neuroimaging Initiative 203
Introduction 203
Alzheimer’ Disease Neuroimaging Initiative 204
Study Outline 205
Preparation Phase 206
Clinical Coordination Center 206
Neuroimaging Core 207
Execution Phase 207
Clinical Core 207
Neuroimaging Core 208
Current State of the ADNI 208
References 209
Two Hits and You’re Out? A Novel Mechanistic Hypothesis of Alzheimer Disease 210
Introduction 210
Oxidative Stress, Oxidative Stress Signaling, and Alzheimer’s Disease 211
Mitotic Abnormalities, Mitotic Signaling, and Alzheimer’s Disease 213
Two-Hit Hypothesis 214
Genetic Factors and the Two-Hit Hypothesis 216
Conclusions 217
References 217
Vascular Risk Factors and Risk for Alzheimer’s Disease and Mild Cognitive Impairment: Population-Based Studies 224
Introduction 224
Subjects and Methods 225
CAIDE Study 225
Kuopio MCI Study 225
Results 225
Vascular Risk Factors in AD and MCI 225
Lifestyle-Related Factors and AD 227
Conclusion 227
References 228
Cholesterol Transport and Production in Alzheimer’s Disease 229
Introduction 229
Cholesterol Homeostasis in the Brain 229
Apolipoprotein E and Cholesterol Transport in the CNS: Backbone for the Maintenance of Synaptic Integrity and Plasticity 231
Cholesterol Homeostasis and Cholesterol-Lowering Drugs 232
Conclusion 235
References 235
Cholesterol and ABeta Production: Methods for Analysis of Altered Cholesterol De Novo Synthesis 238
Introduction 238
Lipids and Alzheimer’s Disease 239
Experiments and Methods 240
Cholesterol De Novo Synthesis Assay 240
Identifying the Target Enzyme 243
Conclusions 244
References 245
Glycosaminoglycans and Analogs in Neurodegenerative Disorders 248
Introduction 248
Synthesis and Physiological Functions of GAG 249
Interactions of sGAG with b-Amyloid Peptide 250
Interaction of sGAG with Tau Protein and Peptides 252
Interaction of sGAG with Prion Protein and Peptides 252
Interaction of SGAG with a-Synuclein 254
Conclusions and Therapeutic Implications 254
References 258
Prospective Role of Glycosaminoglycans in Apoptosis Associated with Neurodegenerative Disorders 263
Introduction 263
Neuroprotective Role of Glycosaminoglycans 263
Role of GAGS in Apoptosis Associated with Neurodegeneration 265
Methods 265
Animals 265
Drugs and Chemicals 265
Administration of drugs and compounds 266
Animal Sacrifice and Tissue Preparation for Histochemical Assays 266
Immunohistochemistry 266
Results 267
Effect of Intracerebroventricular AF64A Administration on Caspase-3 Immunoreactivity 267
AF64A/Saline Administration 267
AF64A/C3 Administration 267
Vehicle of AF64A/C3 Administration 267
Effect of Intracerebroventricular AF64A Administration on ChAT Immunoreactivity 267
AF64A/Saline Administration 267
AF64A/C3 Administration 268
Vehicle of AF64A/C3 Administration 269
Discussion and Conclusion 269
References 269
Stem Cell Therapy in Alzheimer’s Disease 271
Introduction 271
Selection of Stem Cells 272
Transdifferentiation of Adult Stem Cells 272
Dedifferentiation of Adult Stem Cells 274
APP Function in Stem Cell Biology 275
Conclusion 278
References 278
Oral Ab Vaccine Using a Recombinant Adeno-Associated Virus Vector in an Alzheimer’s Disease Mouse Model 281
Introduction 281
Results 282
Production of AAV/Abibeta Vaccine 282
Vaccination and Tissue Examinations 283
Immune Responses to Ab 284
Ab Vaccine-Mediated Meningoencephalitis 284
Gut Immune System and Advantage of AAV/Abibeta Vaccine 285
Mechanism of Abibeta Vaccine 287
Conclusion 287
References 287
In Vivo Targeting of Amyloid Plaques Via Intranasal Administration of Phage Anti-Beta-Amyloid Antibodies 289
Introduction 289
In Vivo Targeting of Amyloid Plaques 290
Passive Immunization of Transgenic Mice with Phage-ScFv Against b-Amyloid Peptide 290
Targeting b-Amyloid Plaques 291
References 293
Decreased ProBDNF: The Cause of Alzheimer’s-Associated Neurodegeneration and Cognitive Decline? 295
Introduction 295
Results 296
Decreased BDNF in AD 296
AD Pathophysiology and BDNF Down-regulation 296
Early BDNF Down-regulation and Functional Deficits in AD 297
Decreased BDNF and Cognitive Decline 297
Conclusions 297
References 298
Shift in the Balance of TRKA and ProNGF in Prodromal Alzheimer’s Disease 300
Introduction 300
Results 301
Preservation of Basocortical Cholinergic Markers in MCI and AD 301
Cholinotrophic Alterations in MCI and AD 301
NGF Receptor Levels in MCI and AD 301
Pro-NGF Increases in MCI and AD 302
Conclusions 303
References 304
Neuroprotective Effects of Trophic Factors and Natural Products: Involvement of Multiple Intracellular Kinases 306
Introduction 306
Neuroprotective Effects of IGF-1 Involved the PI3/AKT Pathway and FOXO3a 307
Effects of Trophic Factors on Other Transcription Factors of the FoxO Family 307
Neuroprotective Effects of Resveratrol Against Aß-Induced Toxicity 308
Tea Extracts Protect Hippocampal Neurons Through Their Catechins Gallate Esters 308
Conclusion 309
References 310
Intraneuronal Abeta and Alzheimer’s Disease 312
Introduction 312
AD Pathology and Cognition 313
Amyloid Cascade Hypothesis 313
Intraneuronal Ab 314
Conclusion 316
References 316
Physiological Processing of the Cellular Prion Protein and betaAPP: Enzymes and Regulation 320
Introduction 320
a-Secretase Processing of betaAPP and PRPC 320
bAPP and PRPC Physiological Processing: Up-regulation by PKC Agonists 322
ADAM10 and ADAM17: Responsible for the Physiological Processing of betaAPP and PRPC? 324
ADAM9: Indirect Contribution to betaAPP and PRPC Physiological Processing by Modulating ADAM10 Activity 326
Conclusion 327
References 328
Expression of Wnt Receptors, Frizzled, in Rat Neuronal Cells 332
Introduction 332
Background 332
References 337
Cell Models of Tauopathy 340
Introduction 340
Results 341
Cell lines 341
Aggregation of Tau in Cells 342
Fragmentation of TauRD by a Thrombin-like Protease 344
Aggregation and Toxicity 345
Reversibility of Aggregation 346
Inhibition of Aggregation by Small Molecule Inhibitors 346
Discussion 348
References 349
Co-expression of FTDP-17 Human Tau and GSK-3Beta (or APPSW) in Transgenic Mice: Induction of Tau Polymerization and Neurodegeneration 352
Introduction 352
Tau Pathology in a Double Transgenic Mouse Overexpressing Tau Bearing Three of the Mutations Present in FTDP-17 (tauVLW) and GSK3 b 353
Tau Pathology in a Double Transgenic Mouse Overexpressing Tau Bearing Three of the Mutations Present in FTDP-17 (TauVLW), and APP Bearing the Swedish Mutation (APPSW) 354
Conclusion 355
References 356
Enhanced Activation of NF-bkappaB Signaling by Apolipoprotein E4 358
Introduction 358
Materials and Methods 359
Transgenic Mice 359
Intracerebroventricular Injection of LPS 359
Immunohistochemistry 360
Results 360
Discussion 365
Conclusion 366
References 367
Pleiotropic Effects of Apolipoprotein E in Dementia: Influence on Functional Genomics and Pharmacogenetics 369
Introduction 369
Functional Genomics Studies 370
Pleiotropic Effects of ApoE 370
ApoE-Related Lipid Metabolism and Atherosclerosis 375
Potential Interactions of ApoE with Liver Function and Drug Metabolism 375
Pharmacogenetics 375
CYP2D6 Polymorphisms in Alzheimer’s Disease 377
Association of ApoE Genotypes with CYP2D6-Related Phenotypes 379
Conclusions 379
References 379
Up-regulation of the balpha-Secretase Pathway 382
Introduction 382
Disintegrin Metalloproteinase ADAM10 as alpha-Secretase In Vivo 382
Up-regulation of the alpha-Secretase Pathway 383
Activation of G Protein-Coupled Receptors and Downstream Signaling Systems 383
Characterization of the Human ADAM10 Promoter and Up-regulation of Gene Expression by Retinoic Acid 384
References 386
Frequency and Relation of Argyrophilic Grain Disease and Thorn-Shaped Astrocytes in Alzheimer’s Disease 388
Introduction 388
Materials and Methods 389
Results 389
Immunohistochemistry 389
Semiquantitative Evaluation of 4R Tauopathy and TSA 390
Frequency of AGD and TSA in AD 390
Relation of AGD and TSA with AD Type Pathology 391
Relation of AGD and TSA with 4R Tau Score in AD 391
Conclusions 392
References 392
Cellular Membranes as Targets in Amyloid Oligomer Disease Pathogenesis 393
Introduction 393
The Case for Oligomers 394
Plasma Membrane as the Primary Target 394
Conclusions 396
References 396
Ganglioside-Dependent Generation of a Seed for Alzheimer’s Disease Amyloid 399
Introduction 399
GAb as Seed for Alzheimer Amyloid 400
Monoclonal Antibody Specific to GAb 400
Immunological Detection of GAb in Brain 400
Background to GAb Generation in Brain 401
GAb as Determinant for Area-Specific Deposition of Abeta 402
Conclusion 403
References 403
Evidence That Amyloid Pathology Progresses in a Neurotransmitter-Specific Manner 405
Introduction 405
Neurotransmitter-Specific Structural Vulnerabilities to Extracellular Ab Burden 405
Amyloid Dependent Neurotransmitter-Specific Dystrophic Neurite Generation 408
Conclusion 410
References 410
Rationale for Glutamatergic and Cholinergic Approaches for the Treatment of Alzheimer’s Disease 414
Introduction 414
Cholinergic Changes in AD 414
Glutamatergic Changes in AD 416
Cholinergic-Glutamatergic Interactions 418
Conclusions 418
References 418
Cortical Cholinergic Lesion Causes ABeta Deposition: Cholinergic-Amyloid Fusion Hypothesis 421
Introduction 421
Methods 423
Cholinergic Therapy of Normal Animals 423
Immunotoxin Lesion of the nbm 423
Cholinergic Therapy of Immunotoxin-Lesioned Animals 425
Results 426
Cholinergic Therapy of Normal Animals 426
Immunotoxin Lesion of the nbm 426
Cholinergic Therapy of Immunotoxin-Lesioned Animals 429
Conclusions 430
References 431
Expression of Acetylcholinesterase in Alzheimer’s Disease Brain: Role in Neuritic Dystrophy and Synaptic Scaling 438
Introduction 438
Effect of Ab on AChE Levels 439
Role of a7 Nicotinic Acetylcholine Receptors in AD 440
Cholinergic Neurites in AD Plaques 441
Do AChE Inhibitors Correct Cholinergic Deficiency? 442
Role of Cholinergic Neurons in Synaptic Scaling 442
Conclusion 443
References 444
Role of B-Amyloid in the Pathophysiology of Alzheimer’s Disease and Cholinesterase Inhibition: Facing the Biological Complexity to Treat the Disease 447
Introduction 447
Effect of Muscarinic Cholinergic Receptor Stimulation on Nonamyloidogenic Metabolism of AbPP 448
Effect of AChEIs on Expression and Metabolism of AbPP 449
Evidence of Gene Expression Modulation by AChEIs 450
Conclusions 451
References 451
Dissociation Between the Potent bbeta-Amyloid Protein Pathway Inhibition and Cholinergic Actions of the Alzheimer Drug Candidates Phenserine and Cymserine 453
Introduction 453
Methods 455
Chemicals 455
Lipophilicity Determination 455
Cell Culture 456
LDH and MTT Assays 456
APP Measurement 456
Ab Assay 456
Cholinesterase Measurements 457
Results 457
Phenserine, Cymserine, and Physostigmine Assessed at Nontoxic Doses in Human Neuronal (SK-N-SH) Cell Cultures 457
Effect of Phenserine, Cymserine, and Physostigmine on Cell Viability 458
Differential Effects of Phenserine, Cymserine, and Physostigmine on Soluble APP Levels 458
Differential Effects of Phenserine, Cymserine, and Physostigmine on Soluble Ab 459
Effects of Phenserine and Physostigmine on Cholinesterase Inhibition 460
Pharmacologic Properties of Three Closely Related Carbamate Drugs 461
Discussion 462
Conclusion 466
References 467
Allosteric Potentiators of Neuronal Nicotinic Cholinergic Receptors: Potential Treatments for Neurodegenerative Disorders 471
Introduction 471
Materials and Methods 472
Fluorescent Imaging Plate Reader 472
Patch-Clamp Recordings in Cultured Hippocampal Neurons 473
Results 474
CNS Selective nAChRs Potentiators 474
Selective ba7 nAChR Potentiators 476
Discussion 477
References 479
Index 481