Neurochemical Mechanisms in Disease (eBook)

John P. Blass (Herausgeber)

eBook Download: PDF

2010 | 2011
XV, 844 Seiten
Springer New York (Verlag)
978-1-4419-7104-3 (ISBN)

Infos

This newest volume of Advances in Neurobiology deals with the Neurochemistry of disease, with chapters covering both human diseases and animal 'model' diseases.

John P Blass, MD, PhD, has been studying the chemistry of diseases of the brain for over half a century: as an undergraduate at Harvard, as a graduate student with Henry McIlwain, as a postdoctoral fellow first with Heinrich Waelsch and then with Daniel Steinberg, during eight years at the Mental Retardation Center at UCLA, and since 1978 as Burke Professor of Neurology, Neuroscience, and Medicine at Weill Cornell Medical College in New York City (now professor emeritus). His work has concentrated on the role of reductions in brain metabolism in Alzheimer's disease and other disorders impairing cognition.

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This newest volume of Advances in Neurobiology deals with the Neurochemistry of disease, with chapters covering both human diseases and animal "e;model"e; diseases.

Inhalt

Preface 4
References 7
Contents 8
Contributors 10
Mechanisms Versus Diagnoses 15
1 Introduction 16
1.1 Focus of This Volume 16
1.1.1 Contrasts Between Science and Clinical Medicine 16
1.1.2 Utility of the Disease Concept 17
1.2 Historical Background 17
1.2.1 Hippocratic Tradition 18
1.2.2 Theory of Humors 18
1.2.3 Sydenham's Conceptualization of Specific Diseases 18
1.2.4 Chemical and Biological Refinements of Sydenham's Concepts 19
1.2.5 Molecular Studies and Clinical Specificity 20
1.3 Example 1: Tay--Sachs Disease 20
1.3.1 Clinical Patterns 21
1.3.2 Neuropathology, Neurochemistry, and Molecular Biology 21
1.3.3 Genetic Variability 21
1.3.4 Variations in Clinical Phenotype 22
1.4 Example 2: Psychoses 23
1.4.1 Recognizing Psychosis 23
1.4.2 Classification of Psychoses 24
1.4.3 The DISC1 Locus 24
1.4.4 Other Loci 24
1.4.5 Modifier Loci 25
1.4.6 Implications for Research on Mental Illness 25
1.5 Example 3: Multiple Sclerosis and Demyelination 26
1.5.1 Clinical Patterns 26
1.5.2 Proposed Mechanisms 26
1.5.3 Chemistry of Demyelination 27
1.6 Implications 27
References 28
Molecular Mechanisms of Neuronal Death 30
1 Introduction 31
2 Caspases: Key Players in Apoptosis 32
2.1 Caspase Activation 33
2.2 Mechanisms of Activation 33
2.2.1 Effector Caspases 33
2.2.2 Initiator Caspases 33
2.3 The Apoptosome 34
2.4 The DISC 34
2.5 The PIDDosome 35
2.6 The Inflammasome 36
3 Apoptotic Routes: Intrinsic and Extrinsic Pathways 36
3.1 The Extrinsic or Receptor-Mediated Pathway 36
3.1.1 TNF Pathway 36
3.1.2 FAS Pathway 38
3.1.3 TRAIL Pathway 39
3.2 The Intrinsic Pathway 39
4 Natural Inhibitors of Caspase Activity 41
4.1 The Inhibitor of Apoptosis Proteins 41
4.2 Natural Inhibitors of the Inhibitor of Apoptosis Proteins: IAP Antagonists 44
4.3 Phosphorylation 44
4.4 Nitrosylation 45
5 ER-Stress 45
6 Crosstalk Between the Intrinsic and Extrinsic Pathways 46
7 Neurodegenerative Diseases: An Example of Dysregulated Apoptosis 47
7.1 Alzheimer's Disease (AD) 48
7.2 Amyotrophic Lateral Sclerosis (ALS) 49
8 Dissecting Death Pathways in Vivo 51
References 52
Animal Models of Neurodegenerative Diseases 61
1 Introduction 62
2 Alzheimers Disease (AD) 64
2.1 The Human Disease 64
2.2 Rodent Models 65
2.2.1 Pharmacological Models of Alzheimer's Disease 65
2.2.2 Transgenic Mouse Models of Alzheimer's Disease 65
2.2.3 Transgenic Rat Models of Alzheimer's Disease 72
2.3 Invertebrate Models 74
2.4 Primate Models 75
2.4.1 Spontaneous Approaches 75
2.4.2 Lesioning Approaches 75
2.4.3 Pharmacological Approaches 76
2.5 Perspectives 76
3 Parkinsons Disease (PD) 77
3.1 The Human Disease 77
3.2 Rodent Animal Models 78
3.2.1 The 6-OHDA Model 78
3.2.2 The MPTP Model 80
3.2.3 Genetic Rodent Models of PD 81
3.3 Nonhuman Primate Models 84
4 Multiple System Atrophy (MSA) 85
4.1 The Human Disease 85
4.2 Rodent Animal Models 86
4.3 Primate Animal Models 88
5 Amyotrophic Lateral Sclerosis (ALS) 88
5.1 The Human Disease 88
5.2 Animal Models 89
6 Huntingtons Disease (HD) 91
6.1 The Human Disease 91
6.2 Rodent Animal Models 92
6.3 Invertebrate Animal Models 94
6.4 Primate Animal Models 95
6.4.1 Lesioning Approaches 95
6.4.2 Genetic Approaches 95
7 Conclusion 96
References 97
Vitamins Deficiencies and Brain Function 114
1 Introduction 114
2 Thiamine (Vitamin B1) 115
2.1 Thiamine Deficiency-Related Neurological Disorders 116
2.2 Thiamine and Cell Metabolism/Function 117
2.2.1 Thiamine as Enzyme Cofactor 117
2.2.2 Thiamine as a Component of Neural Membranes 119
2.3 Neuronal Cell Death in Thiamine Deficiency 119
2.3.1 Cellular Energy Failure 119
2.3.2 Oxidative/Nitrosative Stress 120
2.3.3 NMDA Receptor-Mediated Excitotoxicity 120
2.3.4 The Blood--Brain Barrier Disruption 121
3 Pyridoxine (Vitamin B 6) 121
4 Cobalamin (Vitamin B12) 123
5 Niacin (Vitamin B3) 125
6 Folic Acid (Vitamin B9) 126
7 Antioxidant Vitamins 127
7.1 -Tocopherol (Vitamin E) 127
7.2 Ascorbic Acid (Vitamin C) 129
7.3 Carotenoids 131
References 131
Brain Edema in Neurological Diseases 136
1 Introduction 137
2 Water Homeostasis in the Brain: Physiology of the Brain Fluids 138
3 The Neurovascular Unit and Tight Junction Proteins 139
4 Cytotoxic Brain Edema 144
5 Vasogenic Brain Edema 144
6 Role of Aquaporins in Brain Edema 145
7 Injury Cascade in Brain Edema: Molecular Mechanisms 147
7.1 Cation Channels Involved in Cytotoxic Edema 148
7.2 Role of MMPs in the Formation of Vasogenic Edema 149
7.3 Oxidative Stress and Brain Edema 150
7.4 Involvement of Vasopressin in Cerebral Edema 152
7.5 Vascular Endothelial Growth Factor and Angiopoietins 153
7.6 Bradykinin 154
7.7 Arachidonic Acid and Brain Edema 155
8 Imaging Brain Edema 156
8.1 Imaging by CT 156
8.1.1 Noncontrast-Enhanced CT (NECT) 157
8.1.2 Perfusion CT 157
8.2 Imaging by MRI 159
8.2.1 T2-Weighted Imaging 159
8.2.2 Diffusion-Weighted Imaging (DWI) 159
8.2.3 Diffusion Tensor Imaging (DTI) 161
8.2.4 Susceptibility-Weighted Imaging (SWI) 161
9 Clinical Conditions Associated with Brain Edema 161
10 Treatment of Brain Edema 164
11 Conclusions 166
References 166
Monoamine Transporter Pathologies 180
1 Introduction to Monoamine Transporters 181
1.1 The Monoamine Transporter Family 182
1.2 Neuroanatomy 183
1.3 Physiological Functions 184
1.4 Structure and Transport Mechanism 184
1.5 Vesicular Monoamine Transporters 186
2 Regulation of Plasma Membrane Monoamine Transporters 186
3 Transporter Gene Polymorphisms 188
3.1 NET 188
3.2 DAT 189
3.3 SERT 190
4 Addiction 191
4.1 Psychostimulant Addiction 191
4.2 Alcoholism Alcoholism 192
5 Anxiety and Depression Depression 193
6 Autism 195
7 Parkinsons Disease (PD) 195
8 Important Findings and the Need for Future Studies 196
References 197
Glutamate and Glutamine in Brain Disorders 205
1 Introduction 206
2 Methodological Approaches in the Study of Glutamate and Glutamine Homeostasis in the Brain 208
3 Glutamate and Glutamine Homeostasis in Selected Brain Disorders 209
3.1 Epilepsy 209
3.2 Ischemic Conditions 211
3.3 Neurodegenerative Disorders 213
3.4 Psychiatric Disorders 215
4 Potential Drug Targets Related to Glutamate and Glutamine Homeostasis 217
5 Concluding Remarks 217
References 218
Rho-Linked Mental Retardation Genes 223
1 Mental Retardation 224
1.1 Definition, Causes, and Classification 224
1.2 Mental Retardation Is Associated with Abberations in Spine Structure and Synaptic Function 225
2 Rho GTPases 227
2.1 Rho GTPases Control Synaptic Structure and Function 227
2.2 Mutations in Regulators and Effectors of Rho GTPases Underlie Various Forms of Mental Retardation 231
2.2.1 Oligophrenin-1 (OPHN1) 232
2.2.2 p21-Activated Kinase 3 (PAK3) 234
2.2.3 Rho Guanine Nucleotide Exchange Factor 6 (ARHGEF6) 237
2.2.4 CYFIP/Rac/PAK and Fragile X Syndrome 238
2.2.5 Oculocerebrorenal Syndrome of Lowe Protein 1 (OCRL1) 240
2.2.6 Mental-Disorder-Associated GAP (MEGAP) 241
3 Conclusions 242
References 242
Cognitive Deficits in Neurodegenerative Disorders: Parkinsons Disease and Alzheimers Disease 252
1 Introduction 254
2 Parkinsons Disease: An Overview 255
3 Neurobiology of Parkinsons Disease 257
3.1 Etiology and Molecular Progression of PD 257
3.2 PD as a Synucleinopathy 257
4 Basal Ganglia Circuit 258
4.1 Central Role of Dopamine in PD 258
4.2 The Classical Basal Ganglia Circuit 259
5 Frontal Cortices, Striatum, and Cognition in PD 261
5.1 Fontostriatal Circuits in PD 261
5.2 Impaired Memory in PD: Thalamocortical Circuitry 262
5.3 Genetic Variability of Catechol-O-Methyltranferase, Prefrontal Cortex, and Cognition 264
6 Vision and Visual Cognition 265
6.1 Short-Term Memory for Visual Stimuli and Spatial Orientation in PD 265
6.2 Aging and Cognitive Event-Related Potentials 268
6.3 Neurotransmitters and Cognitive ERP-S in PD 268
6.4 Dopamine in Visual Processing in the Retina 269
6.5 Retinal Model of Dopaminergic Dysfunction in PD 271
7 Nondopaminergic Signals and Cognition in PD 274
7.1 GABA and the Subthalamic Nucleus 274
7.2 Cholinergic Mechanisms 275
7.3 Glutamate, Thalamocortical Processing, and D1 and D2 Dopamine Receptors 276
7.4 Adenosine 277
8 The Alzheimers Disease Case: An Overview 278
9 Cognitive Decline in the Elderly Is It Aging, MCI, or Early AD
9.1 Normal Aging 279
9.2 Mild Cognitive Impairment (MCI) 281
9.3 Predicting Conversion from ?Normal Aging? to MCI and from MCI to AD? 281
9.4 Diagnosis of AD 282
9.5 Diet in AD 283
10 Imaging AD 283
10.1 Can Neuronal Dysfunction Be Visualized Before Cell Death 283
11 APP Processing and Its Relation to Cognition 285
11.1 Amyloid Hypothesis 285
11.2 A? Extra- or Intracellular and in Which Compartment? 286
12 Revisiting the Unforgettable Tau 287
12.1 A and Tau Interaction 287
13 Synaptic Dysfunction in AD 288
13.1 Is AD a Neuronal Disconnection Syndrome? 288
14 Future Perspectives 290
References 291
NF-.B in Brain Diseases 302
1 Introduction 303
2 Structure of NF-B and IB Family 304
3 General Biological Role of NF-B 306
4 Regulation of NF-B Signaling 308
5 Role of NF-B Signaling in the CNS 310
5.1 NF-B in the CNS 310
5.2 Activators and Inhibitors of NF-B in the CNS 310
5.3 NF-.B–Regulating Genes in the CNS 311
5.4 Role of NF-.B in Synaptic Transmission 311
5.5 Role of NF-.B in Learning and Memory 312
5.6 Role of NF-.B in Neuroprotection 312
5.7 Role of NF-.B in Glial Cells 313
6 Role of NF-B in Brain Diseases 314
6.1 Role of NF-.B in Ischemic and Traumatic Brain Injury 314
6.2 Role of NF-.B in Seizures 315
6.3 Role of NF-.B in Alzheimer Disease (AD) 315
6.4 Role of NF-.B in Parkinson’s Disease (PD) and Huntington’s Disease (HD) 316
6.5 Role of NF-.B in Multiple Sclerosis 317
7 NF-B Signaling Pathway as a Potential Therapeutic Target 317
References 319
Trinucleotide-Expansion Diseases 327
1 Introduction 330
2 Diseases Due to a Noncoding Trinucleotide Expansion 330
2.1 Fragile X Syndrome (FRAXA) 331
2.2 Other ''Fragile'' Syndromes 332
2.3 Myotonic Dystrophy Type 1 (DM1) 332
2.4 Friedreich Ataxia (FRDA) 333
2.5 Spinocerebellar Ataxia Type 8 (SCA8) 335
2.6 Spinocerebellar Ataxia Type 12 (SCA12) 336
3 Diseases Due to a Coding Trinucleotide ExpansionPolyglutamine (Qn)-Expansion Diseases 336
3.1 Spinobulbar Muscular Atrophy (SBMA Kennedy Disease)
3.2 Huntington Disease (HD) 339
3.3 Spinocerebellar Ataxia Type 1 (SCA1) 339
3.4 Spinocerebellar Ataxia Type 2 (SCA 2) 340
3.5 Spinocerebellar Ataxia Type 3 (SCA3 Machado--Joseph Disease)
3.6 Dentatorubral Pallidoluysian Atrophy (DRPLA Haw River Syndrome)
3.7 Spinocerebellar Ataxia Type 6 (SCA 6) 341
3.8 Spinocerebellar Ataxia Type 7 (SCA7) 342
3.9 Spinocerebellar Ataxia Type 17 (SCA17) 342
4 Possible Factors Contributing to Neurodegeneration in the (CAG) n/Qn-Expansion Diseases 343
4.1 Toxic Protein Aggregates 343
4.2 Disrupted Proteasome Function 345
4.3 Interference with Gene Expression 346
4.4 Interference with Mitochondrial Function 347
4.5 Aberrant Caspase Activity 348
4.6 Increased Excitotoxicity/Oxidative Stress 349
4.7 Defects in Axonal Transport 350
4.8 Integration of Mechanisms 350
4.9 Therapeutic Strategies 352
5 Diseases Due to a Coding Trinucleotide ExpansionPolyalanine (An)-Expansion Diseases 352
5.1 General Description 352
5.2 Comparison of An-Expansion Diseases with Qn-Expansion Diseases 353
6 Possible Mechanisms Contributing to An-Expansion Diseases 354
7 Other Nucleotide-Expansion Diseases 355
8 Conclusions 356
References 357
CNS Cytokines 367
1 Introduction 368
1.1 Cytokines and Neuroinflammation 369
1.1.1 Interleukin (IL)-1, IL-6, and TNF- 369
1.1.2 IL-18 371
1.1.3 Transforming Growth Factor-Beta (TGF-) 372
1.1.4 IL-33 and HMGB1 373
1.1.5 IL-10 and IL-13 374
1.2 MAP Kinases and Stress Kinases 374
1.3 Microglia Cells 376
1.4 Astrocytes 377
1.5 Neuroinflammatory Aspects of Pb Toxicity 377
1.5.1 Pb Effects on Glial Cells 377
1.5.2 Pb Effects on Cytokines in the CNS 378
1.6 Neuroinflammatory Effects of Metals Other than Pb 380
2 Summary 382
References 383
Neurochemistry of Autism 391
1 Introduction 392
2 Serotonin 392
3 Dopamine 394
4 Acetylcholine 395
5 GABA and Glutamate 396
6 Oxytocin 397
7 Reelin in Autism 398
8 Conclusion 399
References 399
RNA Pathologies in Neurological Disorders 407
1 Introduction 408
2 Physiology of Splicing Mechanisms 409
3 Disorders Associated with Disruption of Splicing Cis-Elements 410
3.1 Aberrations of the 5' Splice Sites 410
3.2 Human Branch Point Consensus Sequence 411
3.3 Ectopic AG Dinucleotide Abrogates the AG-Scanning Mechanism 412
3.4 Mutations That Disrupt ESEand ESS 412
3.5 Mutations That Disrupt ISE and ISS 413
3.6 Spinal Muscular Atrophy (SMA) 413
4 Skipping of Multiple Exons Caused by a Single Splicing Mutation 414
4.1 Skipping of Multiple Contiguous Exons 414
4.2 Nonsense-Associated Skipping of a Remote Exon (NASRE) 414
5 Disorders Associated with Dysregulation of Splicing Trans -Factors 415
5.1 Myotonic Dystrophy 415
5.2 Alzheimer's Disease (AD) and Frontotemporal Dementia with Parkinsonism Linked to Chromosome 17 (FTDP-17) 417
5.3 Facioscapulohumeral Muscular Dystrophy (FSHD) 417
5.4 Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) 418
5.5 Prader--Willi Syndrome (PWS) 418
5.6 Rett Syndrome 418
5.7 Spinocerebellar Ataxia Type 8 (SCA8) 419
5.8 Paraneoplastic Neurological Disorders (PND) 419
References 420
Neurochemistry of Endogenous Antinociception 424
1 Introduction 425
2 Small-Molecules 427
2.1 Class I. Acetylcholine Acetylcholine (ACh) 427
2.1.1 Choline 430
2.2 Class II. Amines 431
2.2.1 Epinephrine (E)/Norepinephrine (NE) 431
2.2.2 Dopamine Dopamine (DA) 432
2.2.3 Serotonin (5-Hydroxi-Tryptamine, 5-HT ) 433
2.2.4 Histamine 435
2.2.5 Melatonin (MT) 436
2.2.6 Agmatine (AGM) 437
2.3 Class III. Amino Acids and Derivatives 438
2.3.1 Glutamate 438
2.3.2 .-Amino-butyric Acid (GABA) 439
2.3.3 Glycine(Gly) 440
2.3.4 D-serine 441
2.3.5 Taurine 441
2.3.6 Kynurenic Acid (KYNA) 442
3 Purines 443
3.1 Adenosine 443
3.2 Nucleotides 444
4 Other Nonpeptide Molecules 445
4.1 Ouabain 445
5 Peptides 446
5.1 Peptide Hormones 446
5.1.1 Oxytocin (OT) 446
5.1.2 Vasopressin (Arginine Vasopressin: AVP) 447
5.1.3 Calcitonin (CT)/Parathyroid Hormone (PTH) /Tuberoinfundibular Peptide of 39 Residues (TIP39) 448
5.1.4 Insulin 448
5.1.5 Renin-Angiotensin System (RAS) 449
5.1.6 Melanocortin System (MC) 449
5.1.7 Corticotropin-Releasing Factor (CRF) and Related Peptides 450
5.1.8 Thyrotropin-releasing Hormone (TRH) 451
5.1.9 Somatostatin (SST) 452
5.1.10 Prolactin 452
5.1.11 Ghrelin 453
5.1.12 Orexins 453
5.1.13 Bombesin-related peptides 454
5.2 Neuropeptides 454
5.2.1 Opioid-Related Peptides 454
5.2.2 Kyotorphin 460
5.2.3 Tachykinins 460
5.2.4 Calcitonin Gene-related Peptide (CGRP) 461
5.2.5 Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) 462
5.2.6 Vasoactive Intestinal Peptide (VIP) 463
5.2.7 Galanin (GAL) 463
5.2.8 Neuropeptide Y (NPY) 464
5.2.9 RFamide neuropeptides 465
5.2.10 Neurotensin (NeT) 466
5.2.11Neurotrophic factors 467
5.3 Other Peptides 470
5.3.1 Endothelins (ET) 470
5.3.2 Hemopressin 470
5.3.3 Annexin-A1 471
5.4 Cytokines 471
6 Lipids 473
6.1 Endocannabinoid System and Related Fatty Acid Derivatives 473
6.1.1 N-Arachidonoyl-Ethanolamine (Anandamide AEA)
6.1.2 2-Arachidonoyl-Glycerol (2-AG) 477
6.1.3 N-Arachidonoyl-Glycine (NAGly) 478
6.1.4 2-Arachidonyl-Glycerylether (Noladin Ether) 479
6.1.5 N-Arachidonoyl-Dopamine (NADA) 479
6.1.6 N-Palmitoyl-Ethanolamide (PEA) and N-Palmitoyl-Glycine (PalGly) 480
6.1.7 N-Oleoyl-Ethanolamide (OEA), N-Oleoyl-Dopamine (OLDA), and Oleamide 481
6.2 Eicosanoids 482
6.3 Gangliosides 483
6.4 Steroids 484
6.4.1 Neurosteroids 484
6.4.2 Sexual Hormones 485
6.4.3 Glucocorticoids 486
7 Gases 487
7.1 Nitric Oxide (NO) 487
7.2 Carbon Monoxide (CO) 489
7.3 Hydrogen Sulfide (H2S) 490
8 Conclusions 491
References 492
Biology of Demyelinating Diseases 543
1 Introduction 544
2 Morphological Aspects 546
2.1 Myelin Structure in the Central and Peripheral Nervous System 546
2.2 Node of Ranvier 547
2.3 Paranode 547
2.4 Myelination 547
2.5 Demyelination 548
2.5.1 Primary Demyelination and Hypomyelination in the CNS. Prospects for Remyelination in MS and leukodystrophies 549
2.5.2 Primary Demyelination and Hypomyelination in the PNS: Charcot-Marie Tooth Diseases (CMT) 550
2.5.3 Ion Channels and Demyelination 551
2.5.4 Astrocytes and Demyelination 551
2.5.5 Experimental Models of Demyelination in the CNS 552
3 Dys- and Demyelination in Relation to Specific Constituents 553
3.1 CNS Myelin Proteins 553
3.2 PNS Myelin Proteins 561
3.3 Proteins and Specific Lipids of the Node of Ranvier and the Paranodal and Juxtaparanodal Areas 563
3.4 Dys- or Demyelination in the CNS and/or the PNS Related to Myelin Lipid Compounds 565
4 Other Glial Cell Types and Factors Involved in Myelination and Demyelination in the CNS 569
4.1 Astrocytes and Mutations in GFAP 569
4.2 Oligodendrocyte Precursors 570
4.3 Biochemical Factors 571
4.3.1 Growth Factors and Transcription Factors 572
5 Conclusion 576
References 577
Brain Protein Oxidation and Modification for Good or for Bad in Alzheimers Disease 590
1 Introduction 590
2 Role of A(1-42) in Oxidative Stress 591
3 Protein Oxidation in AD 593
3.1 Protein Carbonyls in AD Brain 593
3.2 Protein Nitration in AD 595
4 Is Protein Oxidation an Early or Late Event in AD Pathogenesis 601
5 Conclusions 602
References 603
Oxidative Stress and Alzheimer Disease: MechanismsINTbreak and Therapeutic Opportunities
1 Introduction 612
2 Oxidative Stress, Genetics, and Alzheimer Disease Pathology 612
2.1 Fibrillary Aggregates and Oxidative Stress 614
2.2 Amyloid-Peptide 614
2.3 Tau Protein 616
3 Oxidative Stress and Metabolism 617
3.1 Energy Utilization 618
3.2 Mitochondria 618
3.3 Metals 619
4 Current and Future Pharmacological Treatments for Alzheimer Disease 620
5 Conclusion 623
References 623
Tau and Tauopathies 636
1 Introduction 637
2 Biochemistry and Molecular Biology of Tau 638
2.1 Tau Gene 638
2.2 Structure, Cellular Localization, and Putative Functions of Tau Protein 639
2.3 Posttranslational Modifications of Tau 643
2.3.1 Phosphorylation 643
2.3.2 Other Modifications of Tau Proteins 647
2.4 Turnover of Tau Protein 648
3 Tauopathies 649
3.1 Frontotemporal Dementia 650
3.1.1 Spectrum 650
3.1.2 Clinical Features 651
3.1.3 Neuropathology 651
3.1.4 Neurochemistry and Neurobiology 652
3.2 Alzheimer's Disease 652
3.2.1 Clinical Features 652
3.2.2 Neuropathology 653
3.2.3 Neurochemistry and Neurobiology 653
3.2.4 The Tau Isoforms in AD 658
3.3 Progressive Supranuclear Palsy 659
3.3.1 Clinical Features 659
3.3.2 Neuropathology 659
3.3.3 Neurochemistry and Neurobiology 659
3.4 Corticobasalganglionic Degeneration 660
3.4.1 Clinical Features 660
3.4.2 Neuropathology 661
3.5 Multiple System Atrophy (MSA) 661
3.5.1 Clinical Features 661
3.5.2 Neuropathology 662
4 Future Direction 662
4.1 Tau as a Diagnostic Marker 662
4.2 Tau as a Therapeutic Target 663
4.3 Research Avenues 663
References 664
Zinc and Zinc Transport and Sequestration ProteinsINTnl in the Brain in the Progression of Alzheimer
1 Introduction 671
1.1 Clinical Parameters of Mild Cognitive Impairment (MCI), Early AD (EAD), and Late Stage AD (LAD) 672
1.2 Pathological Characterization of MCI, EAD, and LAD 673
2 Zinc and Zinc Homeostasis 674
2.1 Zinc Transport and Sequestration 675
3 Maintenance of Zinc Homeostasis 676
3.1 Metallothioneins 676
3.2 ZIP Proteins 677
3.3 ZnT Proteins 678
4 Zinc, Zinc Transport, Alzheimers Disease, and Mouse Models of AD 679
5 Zinc and Amyloid Beta (A) Peptide Processing and Aggregation 682
6 Zinc as a Therapeutic Target in AD 683
7 Conclusions and Future Directions 684
References 684
The Genetics of Alzheimer's Disease and Parkinson's Disease 696
1 Alzheimers Disease 697
1.1 Introduction 697
1.1.1 Prevalence and Incidence 697
1.1.2 Clinical Symptoms 697
1.1.3 Clinical Diagnosis 698
1.1.4 Neuropathological Diagnosis 698
1.2 Genetics of Alzheimer's Disease 700
1.2.1 Introduction 700
1.2.2 Genes Associated with Autosomal Dominant Alzheimer's Disease 701
1.2.3 Genes Associated with Risk in Sporadic Alzheimer's Disease 709
1.3 Summary 712
2 Parkinsons Disease 712
2.1 Introduction 712
2.1.1 Prevalence and Incidence 712
2.1.2 Clinical Symptoms 712
2.1.3 Clinical Diagnosis 713
2.1.4 Neuropathological Diagnosis 713
2.2 Genetics of Parkinson's Disease 713
2.2.1 Introduction 713
2.2.2 Genes Associated with Autosomal Dominant Parkinson's Disease 714
2.2.3 Genes Associated with Autosomal Recessive Parkinson's Disease 722
2.3 Summary 732
References 733
Nicotinic Receptors in Brain Diseases 757
1 Introduction 758
1.1 Brief History 758
1.2 Activation, Desensitization, and Upregulation 759
2 Diseases Associated with Loss of Brain Nicotinic Receptors 760
2.1 Parkinson's Disease 760
2.2 Alzheimer's Disease 761
2.2.1 Altered Expression of nAChRs 761
2.2.2 Interaction of nAChRs with Amyloid 762
3 Diseases Associated with Innate Differences in the Expression of nAChRs 763
3.1 Schizophrenia 763
3.2 Autism 765
4 Genetic Variants of nAChR Subunit Genes and Brain Disease 766
4.1 Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE) 766
4.2 Other Genetic Variants in nAChR Subunit Genes and Their Relation to Diseases of the Brain 767
5 Diseases Where nAChRs Are Implicated by Therapeutic Effects of Nicotine 768
5.1 Tourette Syndrome 769
5.2 Down Syndrome 769
6 Conclusions 770
References 771
Lysosomal Storage Diseases 785
1 Introduction 786
2 Modes of Clinical Presentation 786
3 Diagnostic Confirmation 791
4 Pathophysiological Mechanisms 792
5 Therapeutic Approaches 793
6 Summary 795
References 796
Genetic Signaling in Glioblastoma Multiforme (GBM):INTnl A Current Overview
1 Introduction 799
2 Brain Cancer EtiologyGlioma and GBM 801
3 Brain TumorsSubpopulations of Brain Tumor Stem Cells 803
4 Gene Expression in the Human Brain 804
5 Gene Expression in Brain Cancers 804
5.1 Beta-Amyloid Precursor Protein ( APP) 806
5.2 Caspase-3 807
5.3 Pentraxin-2 (NP2 NPTX2)
5.4 Vascular Endothelial Growth Factor (VEGF) 808
6 Specific Alterations in the Expression of Brain-Enriched Genes 809
7 Micro RNAs (miRNAs): Specific miRNA and mRNA Alterations in Human Brain Cancer 810
8 Therapeutic Strategies for the Clinical Management of Glioma and GBM 812
9 Summary 814
References 815
Index 821

Produkt-Details

• Erscheint lt. Verlag: 1.12.2010
• Reihe/Serie: Advances in Neurobiology
• Reihe/Serie: Advances in Neurobiology
• Zusatzinfo: XVI, 844 p.
• Verlagsort: New York
• Sprache: englisch
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Humanbiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Zoologie
• ISBN-10: 1-4419-7104-1 / 1441971041
• ISBN-13: 978-1-4419-7104-3 / 9781441971043