Contributors ............................................... xxxvii
Abbreviations ............................................... xliii
1. Introducing Neuroimmune Pharmacology ........................ 1
Howard E.Gendelman and Tsuneya Ikezu
References .................................................. 3
Part 1: Immunology of the Nervous System
2. Innate and Adaptive Immunity in Health and Disease .......... 7
Howard E. Gendelman and Eliezer Masliah
References ................................................. 8
3. Anatomical Networks: Structure and Function of the
Nervous System ............................................. 9
Eliezer Masliah
3.1. Introduction .......................................... 9
3.2. Gross Anatomical Structure of the Brain .............. 10
3.2.1. General Organization of the Central
Nervous System ............................... 10
3.2.1.1. Introduction ....................... 10
3.2.1.2. Cerebral Hemispheres ............... 11
3.2.1.3. The Diencephalon ................... 11
3.2.1.4. The Brainstem ...................... 12
3.2.1.5. The Spinal Cord .................... 13
3.2.2. Internal Organization of the Central
Nervous System ............................... 13
3.2.2.1. Projection and Connections in
the Brain .......................... 13
3.2.2.2. Laminar Organization of the
Cerebral Cortex .................... 14
3.2.2.3. Neuronal Subtypes and Patterns
of Interconnectivity ............... 14
3.3. Cerebrovascular Circulation .......................... 16
3.3.1. Blood Supply to the Central Nervous
System ....................................... 16
3.3.2. Immune Cell Trafficking Through the
Cerebral Vascular Network .................... 17
3.4. Glial Cell Types ..................................... 17
3.5. Brain Regions Linked to Neurodegeneration and
Other Neurological Diseases .......................... 18
Summary .................................................... 19
Review Questions/Problems .................................. 19
References ................................................. 19
4. The Blood Brain Barrier .................................... 21
William A.Banks
4.1. Introduction ......................................... 21
4.2. Development and Structure of the Blood-Brain
Barrier .............................................. 21
4.2.1. Components of the BBB ........................ 21
4.2.1.1. Vascular BBB ....................... 22
4.2.1.2. Choroid Plexus ..................... 22
4.2.1.3. Tanycytic Barrier .................. 22
4.2.2. Perinatal Development and Special
Characteristics of the Neonatal BBB .......... 22
4.2.3. Concept of the Neurovascular Unit and
Comparison to Peripheral Vascular Beds ....... 23
4.3. Mechanisms of Transport Across the BBB ............... 23
4.3.1. Blood to CNS ................................. 23
4.3.1.1. Non-Saturable Passage .............. 23
4.3.1.2. Receptor-Mediated and
Saturable Transporters ............. 25
4.3.2. CNS to Blood ................................. 26
4.3.2.1. Non-Saturable ...................... 26
4.3.2.2. Saturable Transport ................ 27
4.4. Neuroimmune Interactions ............................. 27
4.4.1. Receptors that are Expressed on BBB for
Receptor: Ligand Interactions ................ 27
4.4.2. Permeability to Cytokines and Related
Substances ................................... 27
4.4.3. Permeability to Other Neuroimmune
Substances ................................... 28
4.4.4. Permeability to Immune Cells ................. 28
4.4.5. Permeability to Viruses ...................... 28
4.4.6. Secretion of Neuroimmune-Active
Substances ................................... 28
4.4.7. Modulation of BBB Function by Neuroimmune
Substances ................................... 29
4.4.7.1. Agents that Increase
Permeability Through the BBB ....... 29
4.4.7.2. Regulation of BBB Integrity
and Tight Junction Function ........ 29
4.4.7.3. Regulation of Saturable
Transporters ....................... 29
4.5. Role of BBB in Neuroimmune Diseases .................. 30
4.5.1. TNF Transport and EAE ........................ 30
4.5.2. CNS Injuries and Cytokine Transport .......... 30
4.5.3. Antiretrovirals and the BBB .................. 30
4.5.4. Immune Cell Invasion ......................... 30
4.5.5. Efflux of NeuroAIDS-related Proteins
and Cytokines ................................ 30
Summary .................................................... 31
Review Questions/Problems .................................. 31
References ................................................. 32
5. Anterior Chamber and Retina ................................ 39
Leila Kump and Eyal Margalit
5.1. Introduction ......................................... 39
5.2. Anatomy and Physiology ............................... 39
5.3. Anterior Chamber ..................................... 39
5.3.1. Anatomy and Physiology ....................... 39
5.3.2. Anterior Chamber Associated Immune
Deviation (ACAID) ............................ 39
5.3.3. ACAID and Other Forms of Immune
Regulation and Tolerance ..................... 43
5.3.4. ACAID, Ocular Immune Diseases, and
Implications for Therapy ..................... 43
5.4. Retina ............................................... 44
5.4.1. Anatomy ...................................... 44
5.4.2. Anatomy and Physiology: Retino-Cortical
Pathway ...................................... 45
5.4.3. Anatomy and Physiology: Visual Cortex ........ 47
5.4.4. Anatomy and Physiology: Subcortical
Pathways ..................................... 47
5.5. Retinal Immunology ................................... 49
5.5.1. Retinal Antigens and Autoimmunity ............. 49
Summary .................................................... 50
Review Questions/Problems .................................. 50
References ................................................. 51
6. Hippocampus and Spatial Memory ............................. 55
Huangui Xiong
6.1. Introduction ......................................... 55
6.2. Anatomy of the Hippocampus ........................... 55
6.2.1. Dentate Gyrus ................................ 56
6.2.1.1. Cytoarchitecture ................... 56
6.2.1.2. Fiberarchitecture .................. 56
6.2.2. The Hippocampus Proper (CA1-CA3 Fields) ...... 57
6.2.2.1. Cytoarchitecture ................... 57
6.2.2.2. Fiberarchitecture .................. 57
6.2.3. The Subicular Complex ........................ 58
6.3. Role of the Hippocampus in Learning and Memory ....... 58
6.3.1. Memory Functions of the Hippocampus .......... 58
6.3.2. Synaptic Mechanisms of Memory ................ 59
6.3.2.1. Basic Properties of LTP ............ 59
6.3.2.2. Mechanisms of Hippocampal LTP ...... 59
6.3.2.3. Expression of LTP .................. 60
6.4. Neuroimmunomodulation via Hippocampus ................ 60
6.4.1. Lesion of Hippocampus Affects Immunity ....... 61
6.4.2. Immunomodulation of Neuronal Functions
in Hippocampus ............................... 61
Summary .................................................... 61
Review Questions/Problems .................................. 62
References ................................................. 62
7. Glial and Neuronal Cellular Compostion, Biology, and
Physiology ................................................. 65
Kalipada Pahan
References ................................................. 67
8. Astrocytes, Oligodendrocytes, and Schwann Cells ............ 69
Malabendu Jana, Subhajit Dasgupta, Anuja Ghorpade, and
Kalipada Pahan
8.1. Introduction ......................................... 69
8.2. Historical View ...................................... 69
8.3. Development of Astrocytes and Oligodendrocytes
in the CNS ........................................... 69
8.3.1. Generation of Glial Precursor Cells .......... 69
8.3.2. Signaling Events Driving the Precursors
to Functional Cells: Astrocytes and
Oligodendrocytes ............................. 70
8.4. Astrocytes: Biology and Function ..................... 70
8.4.1. Morphology and Markers ....................... 70
8.4.2. Heterogeneous Population of Astrocytes
in the CNS ................................... 70
8.4.3. Physiological Role of Astrocytes in
the CNS ...................................... 71
8.4.3.1. Maintaining CNS Homeostasis ........ 71
8.4.3.2. Supplying Energy ................... 72
8.4.3.3. Organizing the Information
Network in the CNS ................. 72
8.4.3.4. Releasing Neuropeptides and
Neurotrophins ...................... 74
8.4.3.5. Facilitating Neurogenesis .......... 74
8.4.4. Role of Astrocytes in CNS Disorders .......... 74
8.4.4.1. Activation of Astrocytes and
Gliosis ............................ 74
8.4.4.2. Release of Pro-inflammatory
Molecules .......................... 75
8.4.4.3. Do astrocytes Present Antigen
Under Autoimmune Response? ......... 75
8.4.4.4. Formation of Glial Scar: A
Double-Edged Sword ................. 76
8.4.4.5. Trying to Defend Neurons Against
Oxidative Stress and Excitotoxic
Damage ............................. 76
8.4.4.6. Swelling of Astrocytes ............. 76
8.4.4.7. Undergoing Apoptosis Under
Acute Insults ...................... 77
8.5. Oligodendrocytes: Biology and Function ............... 77
8.5.1. Markers and Morphological Characteristics
of Various Developmental Stages of
Oligodendrocytes ............................. 77
8.5.2. Biological Role of Oligodendrocytes
in the CNS ................................... 77
8.5.2.1. Myelinating CNS Neurons ............. 77
8.5.3. Fate of OL in CNS Pathology .................. 80
8.5.3.1. Role of Autoimmune Trigger in
the Death of OL .................... 80
8.5.3.2. Role of Cytokines in the
Death of OL ........................ 80
8.5.3.3. Role of Nitric Oxide in the
Death of OL ........................ 80
8.5.3.4. Role of Oxidative Stress in the
Death of OL ........................ 80
8.5.3.5. Role of Ceramide in the Death
of OL .............................. 80
8.5.4. Regeneration of OL ........................... 81
8.5.4.1. Molecules Involved in the
Regeneration of OL ................. 81
8.5.4.2. Role of Schwann Cells in the
Regeneration of OL ................. 81
8.5.4.3. Role of Thyroid Hormone in the
Regeneration of OL ................. 81
8.6. Schwann Cells (SCs): Peripheral Glia ................. 81
8.6.1. Classification of Schwann Cells (SCs) ........ 81
8.6.2. Schwann Cell Development ..................... 81
8.6.3. Signaling Pathways Involved in Survival,
Migration and Death of SCs ................... 82
8.6.3.1. Survival ........................... 82
8.6.3.2. Migration .......................... 82
8.6.3.3. Death .............................. 82
8.6.4. Differences Between OL and SC ................ 83
8.6.5. Biological Roles ............................. 83
8.6.5.1. Myelinating Peripheral Neurons ..... 83
8.6.5.2. Tissue Repair/Regeneration ......... 83
Summary .................................................... 84
Review Questions/Problems .................................. 84
References ................................................. 85
9. Macrophages, Microglia, and Dendritic Cells ................ 89
Anuja Ghorpade, Howard E.Gendelman, and
Jonathan Kipnis
9.1. Introduction ......................................... 89
9.2. MP Ontogeny .......................................... 89
9.2.1. MP Differentiation and Development ........... 89
9.2.1.1. Histological and
Immunohistochemical
Characterization of Monocytes
and Macrophages .................... 90
9.2.1.2. Microglia .......................... 90
9.2.1.3. DC ................................. 91
9.2.2. MP-Specific Markers and Cellular
Heterogeneity ................................ 91
9.2.3. Heterogeneity of CNS Macrophages and
Microglia .................................... 92
9.2.4. Markers to Distinguish Microglia from
Other Brain Macrophages ...................... 92
9.3. Macrophages and Microglia: Biology and Function ...... 92
9.3.1. The Four R's of Immune Response .............. 93
9.3.2. Phagocytosis and Intracellular Killing ....... 93
9.3.3. Antigen Processing and Presentation .......... 93
9.3.4. Secretion of Immune Factors .................. 94
9.4. Microglia and Neurodegenerative Diseases ............. 94
9.4.1. Overview ..................................... 94
9.4.2. Acute Injury ................................. 95
9.4.3. Multiple Sclerosis ........................... 95
9.4.4. Alzheimer's Disease .......................... 96
9.4.5. HIV-1 -Associated Dementia ................... 97
9.4.6. Parkinson's Disease .......................... 97
9.4.7. Glaucoma and Ocular Disorders ................ 98
9.4.8. Neurogenesis ................................. 99
9.5. Future Perspectives .................................. 99
9.5.1. The Neuroimmune Synapse ...................... 99
9.5.2. TLRs Signaling in Macrophages and
Microglia .................................... 99
9.5.3. DC-Based Vaccines ............................ 99
Summary ................................................... 100
Review Questions/Problems ................................. 100
References ................................................ 101
10. Neuronal and Glial Signaling .............................. 105
Murali Prakriya and Richard J.Miller
10.1. Introduction ........................................ 105
10.2. Electrogenesis and the Action Potential ............. 105
10.2.1. The Resting Membrane Potential .............. 105
10.2.2. The Action Potential ........................ 107
10.2.3. The Sequence of Activation and
Inactivation of Na+ and K+ Channels
During an Action Potential .................. 107
10.2.4. Transmission of Signals Between
Neurons: Voltage-Activated Ca2+ Channels
Mediate Neurotransmitter Release ............ 108
10.2.5. Membrane Properties of Glial Cells .......... 108
10.2.6. The Structure of Channel Proteins ........... 109
10.3. Neurotransmitters and Neurotransmission ............. 110
10.3.1. Classical Neurotransmitters ................. 110
10.3.2. Novel Neurotransmitters ..................... 112
10.4. Neurotransmitter Receptors .................... 114
10.4.1. Ligand-Gated Ion Channels (Ionotropic
Receptors) .................................. 114
10.4.2. G-Protein-Coupled Receptors/GPCRs ........... 116
10.5. Synaptic Plasticity ................................. 118
10.5.1. Long-Term Potentiation (LTP) ................ 119
10.5.2. Depolarization-Induced Suppression of
Inhibition (DSI) ............................ 120
Summary ................................................... 120
Review Questions/Problems ................................. 120
References ................................................ 121
11. The Vertebrate Retina ..................................... 123
Wallace B.Thoreson
11.1. Introduction ........................................ 123
11.2. Anatomy ............................................. 123
11.3. Cell Types .......................................... 124
11.3.1. Rod and Cone Photoreceptor Cells ............ 124
11.3.1.1. Outer Segments and
Phototransduction ................. 124
11.3.1.2. Light Adaptation .................. 125
11.3.1.3. Photoreceptor Inner Segment,
Soma, and Synaptic Terminal ....... 126
11.3.1.4. The Fovea ......................... 126
11.3.1.5. Cones and Cone Opsins ............. 126
11.3.2. Horizontal Cells ............................ 127
11.3.3. Bipolar Cells ............................... 127
11.3.4. Amacrine Cells .............................. 128
11.3.5. Ganglion Cells .............................. 128
11.4. Circuitry ........................................... 128
11.4.1. Edge Detection and Center-Surround
Receptive Fields ............................ 128
11.4.2. Color ....................................... 129
11.4.3. Directional Selectivity ..................... 129
11.4.4. Rod Pathways ................................ 130
11.5. Glia ................................................ 130
11.6. Retinal Pigment Epithelial Cells .................... 130
11.7. Blood Supply ........................................ 131
Summary ................................................... 132
Review Questions/Problems ................................. 132
References ................................................ 133
12. Lymphocytes and the Nervous System ........................ 135
Larisa Y.Poluektova
12.1. Introduction ........................................ 135
12.2. Overview of Embryonic Lymphopoiesis ................. 136
12.2.1. T Cells ..................................... 136
12.2.2. В Cells ..................................... 136
12.2.3. NK Cells .................................... 136
12.2.4. Cells Derived from Hematopoietic
Precursors and Involved in Immune
Responses in the Brain ...................... 136
12.3. Postnatal Development of Lymphocytes ................ 137
12.3.1. Hematopoietic Stem Cells .................... 137
12.3.2. T Cells Development, TCR, MHC, and
CD4-CD8 Commitment .......................... 138
12.3.2.1. The Thymic Epithelial Cells ....... 138
12.3.2.2. T Cells Receptor and CD4/CD8
Commitment ........................ 138
12.3.2.3. NKT-Cell Development .............. 139
12.3.2.4. T Cells and Brain ................. 139
12.3.3. В Cells ..................................... 140
12.3.3.1. Development in Bone Marrow ........ 140
12.3.3.2. Distribution of В Cells and
Function .......................... 140
12.3.3.3. Brain and В Cells ................. 141
12.3.4. Adult NK Cells .............................. 141
12.4. Organization of the Secondary Lymphoid Tissues ...... 141
12.4.1. Embryonic Development of Lymphoid Tissues ... 141
12.4.2. Lymph Node Architecture ..................... 142
12.4.3. Antigen-Presenting Cells in Lymph Node ...... 142
12.4.4. Lymph Node as the Home for Primary
Adaptive Immune Responses and Peripheral
Tolerance ................................... 143
12.4.4.1. Common Rules of Adaptive Immune
Responses ......................... 143
12.4.4.2. CD4+ Cell Polarization ............ 144
12.4.4.3. CD4+ Cells Interaction with
В Cells ........................... 144
12.4.4.4. В Cells Differentiation and
Humoral Immune Responses .......... 144
12.4.4.5. NK Cells in the Lymph Node ........ 145
12.4.4.6. CD8+ T Cells in the Lymph Node .... 145
12.4.4.7. Memory Formation and Vaccines ..... 145
12.4.4.8. Tolerance ......................... 145
12.4.4.9. Immunologic Memory in Brain ....... 146
12.5. Neuro-Immune Interaction ............................ 146
12.5.1. Innervation of Lymphoid Tissue .............. 146
12.5.2. Regulation of Immune Cells Activity by
Neurotransmitters and Neuropeptides ......... 147
Summary ................................................... 147
Review Questions/Problems ................................. 147
References ................................................ 148
13. Stem Cells ................................................ 151
Hui Peng, Nicholas Whitney, Kang Tang, Myron
Toews, and Jialin Zheng
13.1. Introduction ........................................ 151
13.2. Stem Cells, Neural Stem Cells, and Neural
Progenitor Cells .................................... 151
13.2.1. Embryonic Stem Cell ......................... 151
13.2.2. Adult Stem Cell ............................. 151
13.2.3. Neural Stem Cells and Neural
Progenitor/Precursor Cell ................... 152
13.3. Stem Cells and Neurogenesis During Brain
Development ......................................... 152
13.3.1. Determination and Formation on Neural
Tube ........................................ 152
13.3.2. Neural Stem Cells in CNS Development ........ 153
13.3.3. Stem Cells in Adult Neurogenesis ............ 153
13.4. Stem Cell Signaling Pathways for Migration,
Proliferation, and Differentiation .................. 153
13.4.1. Proliferation ............................... 153
13.4.2. Differentiation ............................. 154
13.4.3. Migration Signaling ......................... 155
13.5. Chemokines and Neurogenesis ......................... 155
13.5.1. SDF-1 and its Receptor CXCR4 ................ 155
13.5.2. Other Chemokines and their Receptors ........ 156
13.6. Growth Factors and Neurogenesis ..................... 156
13.6.1. Epidermal Growth Factor and Basic
Fibroblast Growth Factor .................... 156
13.6.2. Brain-Derived Neurotrophic Factor ........... 156
13.7. The Role of Neurotransmitters in the Regulation
of Neurogenesis ..................................... 157
13.7.1. Dopamine in Neurogenesis .................... 157
13.7.2. Serotonin in Neurogenesis ................... 157
13.7.3. Norepinephrine in Neurogenesis .............. 157
13.7.4. GABA in Neurogenesis ........................ 157
13.7.5. Glutamate in Neurogenesis ................... 157
13.7.6. Interaction of Neurotransmitters in
Neurogenesis ................................ 158
13.8. Brain Inflammation and Neurogenesis ................. 158
13.8.1. Inflammation can Suppress Neurogenesis ...... 158
13.8.2. Proregenerative Role of Microglia and
Brain Immunity .............................. 159
13.9. Stem Cell and Neuronal Repair During Brain Injury
and Neurodegenerative Disorders ..................... 159
13.9.1. Huntington's Disease and Alzheimer's
Disease ..................................... 159
13.9.2. Cerebral Ischemia ........................... 160
13.9.3. Parkinson's Disease ......................... 160
13.9.4. Possible Mechanisms of Injury-Induced
Neurogenesis ................................ 161
13.9.5. Functional Significance of Neurogenesis
After Injury ................................ 161
13.10.Neural Stem Cells and their Potential Role in
Transplant Therapy for Neurodegenerative
Disorders .......................................... 161
13.10.1.Stem Cells for Transplant Therapy ........... 161
13.10.2.Progress in Stem Cell Therapy in
Neurological Disorders ...................... 162
13.10.2.1.Parkinson's Disease ............... 162
13.10.2.2.Spinal Cord Injury ................ 162
13.10.2.3.Multiple Sclerosis ................ 163
13.10.2.4.Other Diseases .................... 163
13.11.Future Directions in Neurogenesis for
Neurodegenerative Disorders ......................... 163
13.11.1.Endogenous Adult Stem Cells as a
Therapeutic Strategy ........................ 163
13.11.2.Other Potential Therapeutic Value
of NSC ...................................... 164
Summary ................................................... 164
Review Questions/Problems ................................. 165
References ................................................ 166
14. Neurobiology and Neural Systems ........................... 171
Tsuneya Ikezu and Howard E.Gendelman
14.1. Introduction ........................................ 171
14.2. Neuron .............................................. 171
14.2.1. Axon ........................................ 171
14.2.2. Dendrites and Dendritic Arbors .............. 172
14.2.1. Intracellular Components of Dendrites ....... 172
14.2.2.2. Dendritic Spine ................... 172
14.2.3. Synapse ..................................... 172
14.2.3.1. Synaptic Adhesion ................. 173
14.2.3.2. Presynaptic Terminal .............. 173
14.2.3.3. Active Zones ...................... 173
14.2.3.4. Exocytosis ........................ 173
14.2.3.5. Calcium-Triggered Exocytosis ...... 173
14.2.3.6. Endocytosis: Kiss-and-Run ......... 174
14.2.3.7. Postsynaptic Density .............. 174
14.2.3.8. PDZ Domains ....................... 174
14.2.4. Axonal Transport ............................ 174
14.3. Neuronal Classification ............................. 175
14.3.1. Bipolar Neuron .............................. 175
14.3.2. Unipolar Neuron (Formally Called
Pseudounipolar Neurons) ..................... 175
14.3.3. Multipolar Neurons .......................... 175
14.4. Diversity in Neuronal Transmission .................. 176
14.4.1. Glutamatergic Neurons ....................... 176
14.4.1.1. Glutamate Receptors ............... 176
14.4.1.2. The Metabotropic Glutamate
Receptor Family ................... 176
14.4.2. GABAergic Neurons ........................... 176
14.4.2.1. GABA Receptors .................... 177
14.4.3. Cholinergic Neurons ......................... 177
14.4.3.1. Cholinergic Receptors ............. 177
14.4.4. Serotonergic Neurons ........................ 177
14.4.4.1. Serotonin Receptors ............... 178
14.4.5. Noradrenergic Neurons ....................... 178
14.4.5.1. Adrenergic Receptors .............. 178
14.5. Neuronal Degeneration and Regeneration .............. 178
14.5.1. Wallerian Degeneration ...................... 178
14.5.2. Regeneration ................................ 178
14.6. Glia ................................................ 179
Summary ................................................... 179
Review Questions/Problems ................................. 179
References ................................................ 180
15. Cytokines and Chemokines .................................. 183
Yunlong Huang, Nathan Erdmann, Terry D.Hexum, and
Jialin Zheng
15.1. Introduction ........................................ 183
15.1.1. Classification of Cytokines, Chemokines,
and Growth Factors .......................... 183
15.1.2. Cytokine Families ........................... 183
15.1.2.1. Type I Cytokine Family ............ 183
15.1.2.2. Type II Cytokine Family ........... 183
15.1.2.3. TNF Family ........................ 184
15.1.2.4. IL-1 Family ....................... 184
15.1.2.5. TGF-p Family ...................... 184
15.1.3. Important Sub-families of Cytokines and
Growth Factors .............................. 184
15.1.3.1. Neurotrophic Factor Families ...... 184
15.1.3.2. Growth Factor Families ............ 184
15.1.4. Structure and Classification of
Chemokines and Their Receptors .............. 184
15.1.4.1. CXC Chemokines .................... 185
15.1.4.2. CC Chemokines ..................... 185
15.1.4.3. CX3CL1 ............................ 185
15.1.4.4. XCL1 .............................. 185
15.2. Cytokines and Growth Factors in the CNS ............. 185
15.3. Molecular Mechanisms of Cytokines, Growth
Factors, and Chemokines Activity and Signaling ...... 187
15.4. Cytokines in Neurodegenerative and
Neuroimmunologic Diseases ........................... 189
15.4.1. Cytokines in HAD ............................ 189
15.4.2. Cytokines in MS ............................. 191
15.4.3. Cytokines in AD ............................. 192
15.5. Chemokines in the CNS ............................... 192
15.6. Chemokines and their Receptors in
Neurodegenerative and Neuroimmunologic Diseases ..... 193
15.6.1. Chemokines and Their Receptors in HAD ....... 194
15.6.1.1. HIV-1, Chemokines and HIV-1
Co-receptors ...................... 194
15.6.1.2. Neuroprotective and Neurotoxic
Effects of Chemokines and Their
Receptors in HAD .................. 194
15.6.1.3. Therapeutic Avenues Directed
Toward Chemokines and Their
Receptors ......................... 195
15.6.2. Chemokines and Their Receptors in MS ........ 195
15.6.3. Chemokines and Their Receptors in AD ........ 196
Summary ................................................... 196
Review Questions/Problems ................................. 196
References ................................................ 198
16. CNS Cell Signaling ........................................ 207
Ramendra N.Saha, Keshore R.Bidasee, and Kalipada
Pahan
16.1. Introduction ........................................ 207
16.2. An Introductory Orientation ......................... 207
16.2.1. General Mechanism of Cellular Signal
Transduction ................................ 207
16.2.2. Signaling in CNS: A Complex Web of
Signaling in Various Cell Types ............. 207
16.3. Signals Maintaining Normal CNS Health and
Function ............................................ 208
16.3.1. Major Signaling Pathways Maintaining
CNS Homeostasis ............................. 208
16.3.1.1. Trk Receptor Signaling ............ 208
16.3.1.2. p75NTR Receptor Signaling ......... 208
16.3.1.3. Ca2+Signaling ..................... 209
16.3.2. Signaling in Physiological Events of CNS .... 210
16.3.2.1. Signaling in Neuronal
Plasticity and Memory Formation ... 210
16.3.2.2. Signaling in Axonal Myelination ... 212
16.4. Signaling During Neuroinflammation .................. 212
16.4.1. Neuroinflammation ........................... 212
16.4.1.1. Cells Involved .................... 212
16.4.1.2. Inducers .......................... 213
16.4.2. Signaling for Gliosis ....................... 213
16.4.2.1. Positive-Regulatory Signals ....... 213
16.4.2.2. Negative-Regulatory Signals ....... 215
16.5. Signaling During Neurodegeneration .................. 217
16.5.1. Neurodegeneration ........................... 217
16.5.1.1. Apoptosis in Neurons .............. 217
16.5.1.2. Inducers (Neurotoxins) ............ 217
16.5.1.3. Neuronal Receptors ................ 217
16.5.2. Activation of Anti-Survival Pathways ........ 217
16.5.2.1. Mitochondria-Dependent
Pathways .......................... 218
16.5.2.2. Mitochondria-Independent
Pathways .......................... 218
16.6. Signaling During Neuroregeneration .................. 220
16.6.1. Signals Blocking Axonal Regeneration ........ 220
16.6.1.1. Inhibitor Trio in Myelin:
Nogo, Mag, and Omgp ............... 220
16.6.1.2. Inhibitory Signaling from
Receptor Trio:
NgR-Lingol-p75NTR ................. 220
16.6.2. Signals Inducing Axonal Regeneration ........ 221
Summary .................................................. 221
Review Questions/Problems ................................ 222
References ............................................... 223
Part 2: Nervous System Diseases and Immunity: Clinical
Descriptions
17. Neurodegeneration ......................................... 229
Serge Przedborski
17.1. Introduction ........................................ 229
17.2. Frequency, Lifespan, and Co-Morbidity ............... 229
17.3. Classification ...................................... 230
17.4. Etiology of Neurodegenerative Diseases .............. 231
17.5. Pathogenesis of Neurodegenerative Diseases .......... 232
17.6. Onset and Progression of the Disease ................ 233
17.7. Cell-Autonomous of the Degenerative Process ......... 234
Summary ................................................... 234
Review Questions/Problems ................................. 234
References ................................................ 236
18. Multiple Sclerosis and Other Demyelinating Diseases ....... 239
Samantha S.Soldan, Gregory Wu, Clyde Markowitz,
and Dennis L.Kolson
18.1. Introduction ........................................ 239
18.2. Clinical Features and Diagnosis of Multiple
Sclerosis ........................................... 239
18.3. Epidemiology and Etiology of MS ..................... 240
18.3.1. Genetic Epidemiology ........................ 241
18.3.2. Environmental Epidemiology .................. 242
18.3.3. Immunological Influences .................... 243
18.4. Pathophysiology of MS ............................... 244
18.4.1. Histology and Physiology of MS Lesions ...... 244
18.4.2. Immunopathogenesis of Myelin Damage
in MS ....................................... 244
18.5. Animal Models of MS ................................. 247
18.5.1. Experimental Autoimmune
Encephalomyelitis (EAE) ..................... 247
18.5.2. Viral Models of MS .......................... 248
18.5.2.1. Theiler's Murine
Encephalomyelitis Virus ........... 248
18.5.2.2. Murine Hepatitis Virus ............ 248
18.6. Recent Advances in the Neuroimmunology of MS ........ 249
18.6.1. CD4+CD25+ Regulatory T-Cells (T Regs) ....... 249
18.6.2. В Cell Responses in MS ...................... 249
18.7. Other Demyelinating Diseases of the CNS ............. 249
Summary ................................................... 250
Review Questions/Problems ................................. 250
References ................................................ 252
19. Guillain-Barre Syndrome, Chronic Inflammatory
Demyelinating Polyradiculoneuropathy, and Axonal
Degeneration and Regeneration ............................. 257
Ralf Gold and Klaus V. Toyka
19.1. Introduction ........................................ 257
19.2. Experimental Models ................................. 258
19.3. Pathogenesis of Axonal Damage in GBS and CIDP ....... 258
19.3.1. Neurotrophic Factors and Survival in
the Inflamed Nervous System ................. 258
19.3.2. Cellular Immune Factors ..................... 259
19.3.3. Humoral Immune Factors ...................... 259
Summary .................................................. 260
Review Questions/Problems ................................ 260
References ............................................... 261
20. Guillain-Barre Syndrome ................................... 263
Helmar C.Lehmann and Kazim A.Sheikh
20.1. Introduction ........................................ 263
20.1.1. Historical Background ....................... 263
20.1.2. Classification of GBS Variants .............. 264
20.1.3. Epidemiology ................................ 264
20.1.4. Clinical Features ........................... 264
20.1.4.1. Investigations .................... 265
20.1.4.2. Clinical Course ................... 265
20.1.4.3. Prognosis ......................... 265
20.1.5. Pathology ................................... 266
20.1.6. Treatment ................................... 266
20.2. Pathogenesis of GBS Variants ........................ 267
20.2.1. Acute Inflammatory Demyelinating
Polyradiculoneuropathy (AIDP) ............... 268
20.2.2. Acute Motor Axonal Neuropathy (AMAN) ........ 270
20.2.3. Fisher Syndrome ............................. 272
20.3. Molecular Mimicry Hypothesis ........................ 273
20.3.1. Campylobacter Jejuni ........................ 273
20.3.2. Haemophilus Influenzae ...................... 274
20.3.3. Mycoplasma Pneumoniae ....................... 274
20.3.4. Cytomegalovirus (CMV) ....................... 275
20.3.5. Gaps in Molecular Mimicry Hypothesis ........ 275
Summary ................................................... 275
Review Questions/Problems ................................. 275
References ................................................ 275
21. Autoimmune Disease ........................................ 283
M. Patricia Leuschen
21.1. Introduction ........................................ 283
21.1.1. Autoimmune Nervous System Disease
Processes ................................... 283
21.1.2. Gender and Autoimmune Disorders ............. 284
21.1.3. Demographics ................................ 284
21.1.4. Proposed Mechanisms and Treatment ........... 284
21.2. Autoimmunity as It Applies to the Nervous System ... 285
21.2.1. The Blood-Brain Barrier and Lymphocyte
Trafficking ................................. 285
21.2.2. Inflammation: A Double Edged Sword .......... 286
21.3. Autoimmune Diseases with Nervous System
Involvement ......................................... 286
21.3.1. Rheumatoid Arthritis ........................ 286
21.3.1.1. Epidemiology ...................... 286
21.3.1.2. Multi System Involvement with
Emphasis on Neurologic
Symptoms .......................... 286
21.3.1.3. Hypotheses for Etiology and
Treatment ......................... 287
21.3.2. Sjogren's Syndrome .......................... 287
21.3.2.1. Epidemiology ...................... 287
21.3.2.2. Multi System Involvement with
Emphasis on Neurologic
Symptoms .......................... 287
21.3.2.3. Hypotheses for Etiology and
Treatment ......................... 288
21.3.3. Systemic Lupus Erythematosus ................ 288
21.3.3.1. Epidemiology ...................... 288
21.3.3.2. Multi System Involvement with
Emphasis on Neurologic Symptoms ... 288
21.3.3.3. Hypotheses for Etiology and
Treatment ......................... 288
21.3.4. Alkylosing Spondylitis, Reiter's
Disease, Psoriasis, Crohn's Syndrome,
and Multiple Sclerosis ...................... 289
21.3.4.1. Alkylosing Spondylitis ............ 289
21.3.4.2. Reiter's Syndrome
(Reactive Arthritis) .............. 289
21.3.4.3. Psoriasis ......................... 290
21.3.4.4. Crohn's Disease ................... 290
21.3.4.5. Multiple Sclerosis (MS) ........... 291
21.4. Emerging Concepts ................................... 292
Summary ................................................... 293
Review Questions/Problems ................................. 293
References ................................................ 294
22. NeuroAIDS ................................................. 297
Yuri Persidsky
22.1. Introduction ........................................ 297
22.2. Clinical Manifestations, Epidemiology, and
NeuroAIDS Disease Evolution in the
Antiretroviral Era .................................. 297
22.2.1. Clinical Presentation and Epidemiology ...... 297
22.2.2. Disease Evolution in the Era of
Anti-Retroviral Therapy ..................... 297
22.3. Neuropathology ...................................... 298
22.3.1. HIV Encephalitis ............................ 298
22.3.2. Neuropathology in the Anti-Retroviral Era ... 299
22.3.3. Patterns of Neuronal Injury ................. 300
22.4. Neuropathogenesis of HIV Infection .................. 300
22.4.1. Mechanisms of Neuronal Injury During
HIV-1 CNS Infection ......................... 300
22.4.2. Astrocytes .................................. 301
22.5. HIV-1 Neuroinvasion and Blood-Brain Barrier
Compromise .......................................... 302
22.5.1. Cellular Neuroinvasion and the BBB .......... 302
22.5.2. Modeling the BBB ............................ 302
22.5.3. Adaptive Immunity ........................... 303
22.6. Animal Models ....................................... 303
22.6.1. Simian Immunodeficiency Virus (SIV) ......... 303
22.6.2. Feline Immunodeficiency Virus ............... 303
22.6.3. Small Animal Models ......................... 304
22.6.3.1. Transgenic Mice ................... 304
22.6.3.2. Murine Retroviruses ............... 304
22.6.3.3. Severe Combined Immune
Deficient Mouse Model ............. 305
22.6.3.4. NOD/SCID and Studies of
Acquired Immune Responses ......... 305
Summary ................................................... 306
Review Questions/Problems ................................. 306
References ................................................ 307
23. HTLV-mi ................................................... 313
Kazunori Fugo, Christian W.Grant, and Steven
Jacobson
23.1. Introduction ........................................ 313
23.2. Structure and Gene Regulation of HTLV-I/II .......... 313
23.3. Clinical Features and Epidemiology of
HTLV-Associated Myelopathy and Tropical Spastic
Paraparesis (HAM/TSP) ............................... 314
23.4. Pathophysiology in CNS .............................. 315
23.5. Immune Response to HTLV-MI .......................... 318
23.6. Animal Models of HTLV-I/II Infection ................ 320
Summary ................................................... 320
Review Questions/Problems ................................. 321
References ................................................ 322
24. Viral Encephalitis ........................................ 327
Clinton Jones and Eric M. Scholar
24.1. Introduction ........................................ 327
24.2. Herpes Simplex Virus-Mediated Encephalitis (HSE) .... 327
24.2.1. Summary of Herpes Simplex Virus Type 1
Productive Infection ........................ 327
24.2.2. Summary of Latent Infection ................. 327
24.2.3. Epidemiology of Herpes Simplex Viruses ...... 328
24.2.4. Pathogenesis of HSE ......................... 328
24.2.5. Animal Models for Studying HSE .............. 328
24.2.6. Clinical Features of HSE .................... 328
24.2.7. Therapy ..................................... 328
24.3. Varicella Zoster Virus (VZV)-Induced Encephalitis ... 329
24.3.1. Summary of Virus Lifecycle and Virus
Transmission ................................ 329
24.3.2. Latency of VZV .............................. 329
24.3.3. Epidemiology of VZV ......................... 329
24.3.4. Clinical Features of VZV .................... 329
24.3.5. Neurological Disorders Associated with
VZV ......................................... 329
24.3.6. Potential Models to Study VZV
Neuropathogenesis ........................... 330
24.3.7. Therapy ..................................... 330
24.4. Human Cytomegalovirus (CMV)-Induced Encephalitis .... 330
24.4.1. Summary of Virus Lifecycle .................. 330
24.4.2. Epidemiology of HCMV ........................ 330
24.4.3. Pathogenesis and Persistence of HCMV ........ 330
24.4.4. Clinical Features of HCMV ................... 331
24.4.5. HCMV-Induced Encephalitis ................... 331
24.4.6. Treatment ................................... 331
24.5. Therapeutic Agents Available to Treat Herpes
Viruses ............................................. 331
24.5.1. Acyclovir ................................... 331
24.5.2. Valacyclovir ................................ 332
24.5.3. Famciclovir ................................. 332
24.5.4. Ganciclovir ................................. 333
24.5.5. Foscarnet ................................... 333
24.5.6. Cidofovir ................................... 334
24.6. West Nile Virus (WNV)-Induced Encephalitis .......... 334
24.6.1. Summary of Virus Lifecycle and Virus
Transmission ................................ 334
24.6.2. Pathogenesis of Encephalitis ................ 335
24.6.3. Animal Models for WNV ....................... 335
24.6.4. Therapy ..................................... 335
24.7. Other Viruses that Can Induce Encephalitis .......... 335
24.7.1. Flavivirus Family Members that Can
Cause Encephalitis .......................... 335
24.7.1.1. St. Louis Encephalitis Virus ...... 335
24.7.1.2. Japanese Encephalitis Virus ....... 336
24.7.1.3. Murray Valley Encephalitis
Virus ............................. 336
24.7.1.4. Tick-Borne Encephalitis Viruses ... 336
24.7.2. Bunyaviridae and Their Role in
Encephalitis ...................... 336
24.7.2.1. Summary of Bunyaviridae and
Their Replication ................. 336
24.7.2.2. The Bunyavirus Genus and Its
Role in Encephalitis .............. 336
24.7.3. Rabies ...................................... 337
Summary ................................................... 337
Review Questions/Problems ................................. 337
References ................................................ 339
25. Alzheimer's Disease ....................................... 343
Tsuneya Ikezu
25.1. Introduction ........................................ 343
25.2. Clinical Features, Epidemiology, and
Neuropathology ...................................... 343
25.2.1. Symptoms (Memory Loss to Progressive
Dementia) ................................... 343
25.2.2. Diagnosis ................................... 343
25.2.3. Epidemiology ................................ 344
25.2.4. Pathology ................................... 344
25.3. Molecular Pathogenesis .............................. 345
25.3.1. Amyloid Precursor Protein ................... 345
25.3.2. PS 1 and γ-Processing Enzyme Complex ........ 345
25.3.3. APP and PS 1 Animal Models .................. 346
25.3.4. β- and α-Processing Enzymes ................. 346
25.3.5. ApoE ........................................ 346
25.3.6. A β Degrading Enzymes ....................... 347
25.3.7. Neurofibrillary Tangle Formation ............ 347
25.3.8. Neurotoxicity and Synaptic Dysfunction ...... 348
25.3.8.1. Aβ-Mediated Neurotoxicity ......... 348
25.3.8.2. Aβ-Mediated Synaptic
Dysfunction ....................... 348
25.3.8.3. Neurotoxicity by Tau
Aggregation ....................... 348
25.4. Immunity and AD ..................................... 349
25.4.1. Microglia-Mediated Aα Clearance ............. 349
25.4.2. Glial Inflammation and Innate Immunity ...... 349
25.4.2.1. Cytokines ......................... 349
25.4.2.2. Chemokines ........................ 350
25.4.2.3. Toll-Like Receptors ............... 351
25.4.2.4. Matrix Metalloprotease ............ 351
25.4.2.5. Other Inflammatory Molecules:
Complement Complex and CD45 ....... 351
25.4.3. Oxygen Free Radicals ........................ 351
25.4.3.1. Oxidative DNA Damage .............. 352
25.5. Immunopharmacology .................................. 352
Summary ................................................... 352
Review Questions/Problems ................................. 353
References ................................................ 353
26. Parkinson's Disease ....................................... 363
Serge Przedborski
26.1. Introduction ........................................ 363
26.2. Inflammatory Response in Parkinson's Disease ........ 364
26.3. Inflammatory Response in Parkinsonian Syndromes ..... 365
26.4. Inflammatory Response in Experimental Models ........ 365
26.5. Initiation of the Inflammatory Response in
Parkinsonian Brains ................................. 367
26.6. Role of Inflammation in Parkinson's Disease ......... 368
26.7. Beneficial Role of Inflammation in Parkinson's
Disease ............................................. 368
26.8. Detrimental Role of Inflammation in
Parkinson's Disease ................................. 369
Summary ................................................... 370
Review Questions/Problems ................................. 371
References ................................................ 372
27. Amyotrophic Lateral Sclerosis ............................. 377
Adam Czaplinski, Albert A.Yen, Ericka P.Simpson,
Stanley H.Appel
27.1. Introduction—Clinical Features ...................... 377
27.1.1. Pathogenesis ................................ 377
27.1.2. Neuroinflammation ........................... 378
27.2. Cellular and Biochemical Evidence of
Neuroinflammation ................................... 378
27.2.1. Human ALS Studies ........................... 378
27.2.2. Animal Models ............................... 380
27.2.3. In Vitro Studies ............................ 380
27.2.4. Conclusions ................................. 381
27.3. The Failure of Immunosuppression in ALS ............. 381
27.4. Evidence for a Role in Initiating Disease ........... 381
27.5. Evidence for a Role in Amplifying Disease ........... 382
27.6. Evidence for a Role in Repair and Protection ........ 382
Summary ................................................... 383
Review Questions/Problems ................................. 383
References ................................................ 385
28. Huntington's Disease ...................................... 389
Gendelman Seymour, Gendelman Howard E., and Ikezu
Tsuneya
28.1. Introduction ........................................ 389
28.2. History ............................................. 389
28.3. Epidemiology ........................................ 390
28.4. Genetics ............................................ 390
28.5. Pathology ........................................... 391
28.6. Clinical Course ..................................... 392
28.6.1. Natural History ............................. 392
28.6.2. Personality—Behavioral Disorder ............. 393
28.6.3. Cognitive Deterioration ..................... 393
28.6.4. Laboratory .................................. 393
28.6.5. Diagnosis ................................... 393
28.6.6. Treatment ................................... 394
28.7. Mechanisms of Cell Death ............................ 394
28.7.1. Neurotoxicity ............................... 394
28.7.2. Biological Function of Htt .................. 394
28.7.3. Polyglutamine Tract/Htt Misfolding and
Neurotoxicity ............................... 396
28.7.4. Htt Oligomer as Potential Pathogenic
Form of HD Neurotoxicity .................... 396
28.8. Glial Inflammation in HD ............................ 397
28.9. Preclinical Studies ................................. 397
Summary ................................................... 397
Review Questions/Problems ................................. 398
References ................................................ 398
29. Prion Diseases ............................................ 403
Qingzhong Kong and Richard A.Bessen
29.1. Introduction and History of Prion Diseases .......... 403
29.2. Prion Protein Gene and Gene Products ................ 404
29.2.1. Prion Protein Gene and PrPc ................. 404
29.2.2. The Protein-Only Hypothesis for the
Prion Diseases .............................. 404
29.2.3. Molecular Classification of PrPsc in
Human Prion Diseases ........................ 405
29.3. Epidemiology and Clinical Features of Human
Prion Diseases ...................................... 406
29.3.1. Sporadic Human Prion Diseases ............... 406
29.3.2. Familial Human Prion Diseases ............... 407
29.3.3. Acquired Human Prion Diseases ............... 408
29.4. Neuropathology of Human Prion Diseases .............. 409
29.5. Peripheral Prion Replication and Neuroinvasion ...... 409
29.5.1. vCJD and Oral Routes of Animal Prion
Transmission ................................ 410
29.6. CNS Pathogenesis of Sporadic, Familial, and
Iatrogenic Prion Diseases ........................... 411
29.6.1. Sporadic CJD ................................ 411
29.6.2. Familial Prion Disease ...................... 411
29.6.3. Iatrogenic CJD .............................. 411
29.7. Prion Agent Interaction with the Immune System ...... 411
29.7.1. Prion Infection of Secondary Lymphoid
Tissues ..................................... 411
29.7.2. Trafficking of the Prion Agent to
Secondary Lymphoid Tissues .................. 412
29.7.3. Trafficking of the Prion Agent to the
Central Nervous System ...................... 412
29.7.4. Role of Inflammation in the Peripheral
Distribution and Transmission of the
Prion Agent ................................. 412
Summary ................................................... 412
Review Questions/Problems ................................. 413
References ................................................ 413
30. Glaucoma .................................................. 415
Deven Tali and Carl B.Camras
30.1. Introduction ........................................ 415
30.2. Epidemiology ........................................ 415
30.2.1. Prevalence .................................. 415
30.2.2. Prognosis ................................... 415
30.2.3. Risk Factors ................................ 416
30.2.3.1. Intraocular Pressure .............. 416
30.2.3.2. Race .............................. 417
30.2.3.3. Age ............................... 417
30.2.3.4. Central Corneal Thickness ......... 417
30.2.3.5. Family History .................... 417
30.2.3.6. Other Factors ..................... 417
30.3. Pathophysiology ..................................... 418
30.3.1. Mechanical Theory ........................... 419
30.3.2. Vascular Theory ............................. 419
30.3.3. Contributory Mechanisms ..................... 419
30.3.3.1. Immune Mechanisms ................. 419
30.3.3.2. Apoptosis ......................... 419
30.3.3.3. Glutamate-Induced
Excitotoxicity .................... 421
30.3.3.4. Free Radicals ..................... 421
30.3.3.5. Nitric Oxide Synthase ............. 421
30.3.3.6. Dopamine Deficiency ............... 421
30.3.3.7. Heat-Shock Proteins ............... 421
30.3.3.8. Activated Microglia ............... 421
30.3.3.9. Genetic Mutations ................. 421
30.4. Clinical Features ................................... 422
30.4.1. History ..................................... 422
30.4.2. Physical Exam ............................... 422
30.4.2.1. Tonometry ......................... 422
30.4.2.2. Gonioscopy ........................ 422
30.4.2.3. Optic Disc and Nerve Fiber
Layer ............................. 423
30.4.2.4. Visual Field Testing .............. 423
30.5. Differential Diagnosis .............................. 424
30.6. Animal Models ....................................... 424
Summary ................................................... 425
Review Questions/Problems ................................. 425
References ................................................ 426
31. Stroke and Cerebrovascular Disease ........................ 429
Alison E.Baird
31.1. Introduction ........................................ 429
31.2. Immunity and the Central Nervous System ............. 430
31.2.1. Immune Surveillance and the Central
Nervous System .............................. 430
31.2.2. Innate and Adaptive Immunity ................ 430
31.3. Ischemic Stroke and Inflammation .................... 431
31.3.1. Involvement of Immune Cells ................. 432
31.3.2. Molecular Mediators of Inflammation ......... 432
31.3.3. Migration of Immune Cells Across the
Blood Brain Barrier ......................... 434
31.3.4. Effects of Ischemic Stroke on the
Systemic Immune System ...................... 434
31.3.5. Tissue Repair and Recovery After
Ischemic Stroke ............................. 436
31.4. Hemorrhagic Stroke and Inflammation ................. 436
31.5. Atherosclerotic Cerebrovascular Disease and
Inflammation ........................................ 437
31.6. Risk Factors for Stroke ............................. 438
31.7. Therapeutic Neuroimmune Pharmacological
Intervention ........................................ 438
31.7.1. Treatment of Ischemic Stroke ................ 438
31.7.2. Treatment of Hemorrhagic Stroke ............. 439
31.7.3. Primary and Secondary Prevention of
Stroke ...................................... 439
Summary ................................................... 440
Review Questions/Problems ................................. 440
References ................................................ 441
32. Neurogenesis and Brain Repair ............................. 445
G.Jean Harry
32.1. Introduction ........................................ 445
32.2. Neurogenesis and Classification of Cells ............ 445
32.2.1. Neural Development .......................... 445
32.2.2. Neurogenic Potential in the Adult ........... 446
32.2.2.1. Subventricular Zone ............... 447
32.2.2.2. Subgranular Zone .................. 448
32.3. Methods Used to Detect Newly Generated Cells ........ 448
32.3.1. Markers Used for Cell Proliferation
and Stem/Progenitor Cells ................... 448
32.3.2. Neural Cell-Specific Markers ................ 449
32.4. Regulatory Factors Influencing Adult
Neurogenesis ........................................ 449
32.4.1. Age ......................................... 450
32.4.2. Life-Style .................................. 450
32.4.3. Endogenous Factors .......................... 450
32.4.3.1. Sex Hormones ...................... 450
32.4.3.2. Growth and Neurotrophic
Factors ........................... 451
32.4.3.3. Cell Adhesion Molecules ........... 452
32.4.3.4. Other Developmental Signaling
Factors ........................... 452
32.5. Contribution of Glial Cells ......................... 453
32.6. Models of Brain Injury Showing Induction
of Neurogenesis ..................................... 454
32.6.1. Olfactory System Damage ..................... 454
32.6.2. Seizure-Induced Neurogenesis ................ 454
32.6.3. Ischemia .................................... 454
32.6.4. Traumatic Brain Injury ...................... 455
32.6.5. Chemical Injury and Damage to Dentate
Granule Neurons in the Hippocampus .......... 455
32.7. Neuroinflammation ................................... 456
Summary ................................................... 456
Review Questions/Problems ................................. 456
References ................................................ 457
33. Familial Neurodegenerative Diseases and Single
Nucleotide Polymorphisms .................................. 463
Michael Slifer and Jeffery M.Vance
33.1. Introduction ........................................ 463
33.2. Background .......................................... 463
33.3. Neurodegenerative Disorders ......................... 465
33.3.1. Alzheimer's Disease ......................... 465
33.3.1.1. Mendelian Genes of Early-Onset
Alzheimer's Disease (EOAD) ........ 465
33.3.1.2. Late-Onset Alzheimer's
Disease (LOAD) and
Susceptibility Genes .............. 466
33.3.1.3. Modifier Genes of LOAD ............ 467
33.3.1.4. Clinical Implications of
Genetic Discoveries for AD ........ 467
33.3.2. Parkinsonian Disorders ...................... 468
33.3.2.1. Parkinson's Disease ............... 468
33.3.2.2. Amyotrophic Lateral Sclerosis
(ALS) ............................. 470
33.3.2.3. Progressive Supranuclear
Palsy (PSP) ....................... 470
33.3.2.4. Frontotemporal Dementia with
Parkinsonism-17 ................... 471
33.3.2.5. Multisystem Atrophy (MSA) ......... 471
33.3.3. Multiple Sclerosis (MS) ..................... 471
Summary ................................................... 471
Review Questions/Problems ................................. 472
References ................................................ 473
34. The Neuroimmune System in Psychiatric Disorders ........... 479
L.Charles Murrin and Mark P.Thomas
34.1. Introduction ........................................ 479
34.2. Neurohormones and Their Receptors Associated
with Both the Central Nervous System and the
Immune System ....................................... 479
34.3. HPA Axis Regulation of CNS Function ................. 480
34.3.1. Hormones Released by the HPA Axis ........... 481
34.3.2. The Role of HPA Axis in Response to
Stress ...................................... 481
34.3.2.1. Modes of the Acute Stress
Response .......................... 481
34.3.2.2. Chronic Stress Response ........... 482
34.3.3. Role of HPA Axis in Inflammation ............ 482
34.3.4. Impact of HPA Axis on Psychiatric
Disorders ................................... 482
34.3.4.1. Major Depression .................. 482
34.3.4.2. Schizophrenia ..................... 482
4.4. Neuropeptides as Modulators of the CNS and
Immune Function ..................................... 483
34.4.1. Peptides Derived from Proenkephalin ......... 483
34.4.1.1. Expression of Enkephalins in
the Immune System ................. 484
34.4.1.2. Function of the Enkephalins in
the Immune System ................. 484
34.4.2. Peptides Derived from Proopiomelanocortin
(POMC) ...................................... 484
34.4.2.1. Expression of POMC in the
Immune System ..................... 485
34.4.2.2. Beta-Endorphin .................... 485
34.4.2.3. a-MSH ............................. 485
34.4.3. Corticotropin Releasing Hormone ............. 485
34.4.4. Nociceptin, Endomorphins, and Urocortins .... 486
34.5. Cytokines as Regulators of the CNS and Immune
Function ............................................ 487
34.5.1. Cytokine Actions in the CNS ................. 487
34.5.2. Cytokines and the HPA Axis .................. 487
34.5.2.1. Interleukin-lp .................... 487
34.5.3. Impact of Immune System Cytokines in
Psychiatric Disorders ....................... 487
34.5.3.1. Role in Major Depression .......... 487
34.5.3.2. Role in Schizophrenia ............. 487
34.6. Overview of the Role of the Neuroimmune System
in Depression and Schizophrenia ..................... 488
34.6.1. Depression and the Immune System ............ 488
34.6.2. Schizophrenia and the Immune System ......... 489
Summary ................................................... 490
Review Questions/Problems ................................. 490
References ................................................ 491
35. Major Depression, Bipolar Syndromes, and
Schizophrenia ............................................. 495
Frederick Petty, Sriram Ramaswamy, Prasad R. Padala,
Jean D. Deupree, and David B. Bylund
35.1. Introduction ........................................ 495
35.2. Major Depressive Disorder ........................... 495
35.2.1. Clinical Diagnosis and Description .......... 495
35.2.2. Diagnostic Criteria ......................... 496
35.2.3. Epidemiology ................................ 496
35.2.4. Course of Illness ........................... 496
35.2.5. Etiology .................................... 497
35.2.6. Neurobiology ................................ 497
35.2.6.1. Biogenic Amine Hypothesis ......... 497
35.2.6.2. Neurotransmitter Receptor
Alterations ....................... 498
35.2.6.3. Neuroendocrine Findings ........... 498
35.2.6.4. Neurophysiological Correlates ..... 499
35.2.6.5. Brain Imaging ..................... 499
35.2.7. Animal Models ............................... 499
35.2.8. Treatment ................................... 499
35.2.9. Immunological Correlates .................... 501
35.3. Bipolar Disorder .................................... 501
35.3.1. Clinical Diagnosis and Description .......... 501
35.3.2. Diagnostic Criteria ......................... 501
35.3.3. Epidemiology ................................ 502
35.3.4. Course of Illness ........................... 502
35.3.5. Etiology .................................... 502
35.3.6. Neurobiology ................................ 503
35.3.7. Animal Models ............................... 503
35.3.8. Treatment ................................... 503
35.3.9. Immunological Correlates .................... 504
35.4. Schizophrenia ....................................... 504
35.4.1. Clinical Diagnosis and Description .......... 504
35.4.2. Diagnostic Criteria ......................... 504
35.4.3. Epidemiology ................................ 504
35.4.4. Course of Illness ........................... 504
35.4.5. Etiology .................................... 505
35.4.6. Neurobiology ................................ 505
35.4.7. Animal Models ............................... 505
35.4.8. Treatment ................................... 506
35.4.9. Immunological Correlates .................... 506
Summary ................................................... 506
Review Questions/Problems ................................. 506
References ................................................ 508
36. Molecular Pathogenesis for Schizophrenia and Major
Depression ................................................ 511
Norbert Müller and Markus J.Schwarz
36.1. Introduction ........................................ 511
36.2. Glutamatergic Neurotransmission and
NMDA-Receptor Function in Schizophrenia
and Major Depression ................................ 511
36.2.1. Schizophrenia ............................... 511
36.2.2. Major Depression ............................ 512
36.3. Inflammation in Schizophrenia and Depression ........ 512
36.3.1. Schizophrenia ............................... 512
36.3.2. Major Depression ............................ 512
36.4. Polarized Type-1 and Type-2 Immune Responses ........ 513
36.4.1. Reduced Type-1 Immune Response
in Schizophrenia ............................ 513
36.4.2. Increased Type-2 Immune Response in
Schizophrenia ............................... 513
36.4.3. Increased Proinflammatory Type-1
Cytokines in Major Depression ............... 513
36.5. Somatic States Associated with Depression and
a Proinflammatory Immune Response
as Psychoneuroimmunological Model Diseases .......... 514
36.5.1. Medical Illness Condition ................... 514
36.5.2. Therapies Using Type-1 Cytokines ............ 514
36.5.3. Pregnancy and Delivery ...................... 514
36.6. Therapeutic Mechanisms and the Type-l/Type-2
Imbalance in Schizophrenia and Depression ........... 515
36.6.1. Schizophrenia: Anti-Psychotic Drugs
Rebalance the Type-l/Type-2 Imbalance ....... 515
36.6.2. Therapeutic Techniques in Depression are
associated with Downregulation of the
Proinflammatory Immune Response ............. 515
36.6.2.1. Antidepressant
Pharmacotherapy ................... 515
36.6.2.2. Non-Pharmacological Therapies:
Electro-Convulsive Therapy and
Sleep Deprivation ................. 515
36.7. Divergent Effects of the Role of Type-l/Type-2
Immune Activation are associated with Different
Effects to the Kynurenine Metabolism in
Schizophrenia and Depression ........................ 515
36.7.1. Schizophrenia ............................... 515
36.7.2. Major Depression ............................ 516
36.8. Astrocytes, Microglia, and Type-l/Type-2
Response ............................................ 517
36.9. The Glutamate System in Schizophrenia and
Depression .......................................... 517
36.9.1. The Glutamate System in Schizophrenia:
Kynurenic Acid as a Schizophrenogenic
Substance ................................... 517
36.9.2. The Glutamate System in Depression:
Quinolinic Acid as a Depressiogenic
Substance ................................... 518
36.10.Prostaglandins in Schizophrenia and Depression ...... 518
36.11.The Role of the Hormones of the
Hypothalamus-Hypophysis-Adrenal-Axis ................ 519
36.12.COX-2 Inhibitors in Schizophrenia and Depression .... 520
36.12.1.Cyclooxygenase-2 (COX-2) Inhibitors
Inhibit the Production of Kynurenic Acid,
Balance the Type-l/Type-2 Immune Response,
and Have Therapeutic Effects in Early
Stages of Schizophrenia ..................... 520
36.12.2.COX-2 Inhibition as a Possible
Antiinflammatory Therapeutic Approach
in Depression ............................... 520
Summary ................................................... 521
Review Questions/Problems ................................. 521
References ................................................ 523
37. Drugs of Abuse and the Immune System ...................... 531
Toby K.Eisenstein, David E.Kaminsky, Rahil
T.Rahim, and Thomas J.Rogers
37.1. Introduction ........................................ 531
37.2. Fundamental Concepts ................................ 531
37.2.1. Opioid and Cannabinoid Receptors are on
Cells of the Immune System .................. 531
37.2.1.1. Opioid Receptors .................. 531
37.2.1.2. Cannabinoid Receptors ............. 532
37.2.2. Mechanisms by Which Drags of Abuse Can
Affect Cells of the Immune System ........... 532
37.3. Functional Consequences of Drugs of Abuse on
the Immune System ................................... 532
37.3.1. Effects on Innate Immunity and the
Inflammatory Response ....................... 532
37.3.1.1. Cells and Molecules of the
Innate Immune Response ............ 532
37.3.1.2. Effects of Opioids,
Cannabinoids, and
Cocaine on NK Cells ............... 533
37.3.1.3. Drugs of Abuse Alter Functions
of PMN Leukocytes and
Monocytes/Macrophages ............. 533
37.3.1.4. Effects of Drugs of Abuse on
the Production of Cytokines
and Chemokines .................... 534
37.3.2. Effects on Adaptive Immunity ................ 535
37.3.2.1. Humoral Immunity
(Antibody Responses) .............. 535
37.3.2.2. T Cell Responses .................. 536
37.4. Effects of Drugs of Abuse on Infection .............. 536
37.4.1. Overview .................................... 536
37.4.2. Effects of Drugs of Abuse on Infections
Other than HIV .............................. 536
37.4.3. Effects of Drugs of Abuse on HIV or
Related Infections .......................... 536
Summary ................................................... 537
Review Questions/Problems ................................. 537
References ................................................ 539
Part 3: Therapeutics
38. Neuropharmacology ......................................... 547
Terry D.Hexum, L.Charles Murrin, and
Eric M.Scholar
38.1. Introduction ........................................ 547
38.2. The Autonomic Nervous System ........................ 547
38.2.1. Anatomy and Physiology ...................... 547
38.2.2. Neurotransmission ........................... 548
38.2.3. Pharmacology of Autonomic Agents ............ 549
38.2.4. Autonomic Regulation of Immunity ............ 550
38.3. CNS Pharmacology .................................... 551
38.3.1. Central Nervous System ...................... 551
38.3.2. Opioid Drugs and Opioid Receptors ........... 551
38.3.2.1. Opioid Receptors .................. 551
38.3.2.2. Endogenous Opioid Neuropeptides ... 552
38.3.2.3. Opioid Drug Effects on the
Immune Systems .................... 552
38.3.3. Sedative-Hypnotic Agents and Drug Abuse ..... 554
38.3.3.1. Benzodiazepines ................... 554
38.3.3.2. Barbiturates ...................... 555
38.3.4. General Anesthetics ......................... 555
38.3.4.1. General Anesthetics and the
Immune System .................... 556
38.4. Immunopharmacologics ................................ 556
38.4.1. Immunostimulating Agents .................... 556
38.4.1.1. Interferons ....................... 556
38.4.1.2. Interleukin-2 (IL-2) .............. 557
38.4.1.3. Immunoglobulin Intravenous
Therapy (IGIV Therapy) ............ 557
38.4.2. Immunosuppressive Agents .................... 557
38.4.2.1. Corticosteroids ................... 557
38.4.2.2. Calcineurin Inhibitors ............ 557
38.4.2.3. Cytotoxic/Antiproliferative
Agents ............................ 558
38.4.2.4. Antibodies ........................ 559
Summary ................................................... 560
Review Questions/Problems ................................. 560
References ................................................ 561
39. Neurodegenerative Diseases ................................ 565
Jinsy A.Andrews and Paul H.Gordon
39.1. Introduction ........................................ 565
39.1.1. Overview of Mechanism ....................... 565
39.1.2. Overview of Animal Models ................... 565
39.2. Disease-Specific Therapy ............................ 566
39.2.1. Alzheimer's Disease ......................... 566
39.2.1.1. Cholinesterase Inhibitors ......... 566
39.2.2. Parkinson's Disease ......................... 567
39.2.2.1. Levodopa .......................... 567
39.2.2.2. Catechol-O-methyltransferase
Inhibitors ........................ 567
39.2.2.3. Dopamine Agonists ................. 567
39.2.2.4. Anticholinergic Agents ............ 568
39.3. Neuroprotective Therapy ............................. 568
39.3.1. Riluzole .................................... 568
39.3.2. Memantine ................................... 569
39.3.3. Selegiline .................................. 569
39.4. Symptomatic Therapy ................................. 569
39.4.1. Psychiatric Symptoms ........................ 571
39.4.2. Sialorrhea .................................. 571
39.4.3. Motor Symptoms .............................. 572
39.4.4. Autonomic Symptoms .......................... 572
39.4.5. Gastrointestinal Symptoms ................... 572
39.4.6. Genitourinary Symptoms ...................... 572
39.4.7. Sleep Disorders ............................. 572
39.5. Current and Future Directions for Neuroprotection ... 573
39.5.1. Anti-Inflammatory Agents .................... 573
39.5.1.1. Nonsteroidal Anti-Inflammatory
Drugs (NSAIDS) .................... 573
39.5.2. Immunomodulation ............................ 573
39.5.2.1. Vaccination in ALS ................ 573
39.5.2.2. Immunization in AD ................ 573
39.5.2.3. Immunotherapy in Prion Disease .... 574
39.5.2.4. Immunotherapy in Parkinson's
Disease ........................... 574
39.5.3. Anti-apoptotic Therapies .................... 574
39.5.3.1. Minocycline ....................... 574
39.5.3.2. TCH 346 (Omigapil) ................ 575
39.5.3.3. Mitogen Activated Protein (MAP)
Kinase Inhibitors ................. 575
39.5.4. Antioxidants ................................ 575
39.5.4.1. Vitamin E ......................... 575
39.5.4.2. Selegiline ........................ 575
39.5.4.3. N-acetylcysteine .................. 575
39.5.4.4. Coenzyme Q10 (CoQIO) .............. 575
39.5.4.5. AEOL 10150 ........................ 576
39.5.5. Trophic Factors ............................. 576
39.5.5.1. Insulin-Like Growth Factor ........ 576
39.5.5.2. Vascular Endothelial Growth
Factor ............................ 576
39.5.5.3. Brain Derived Growth Factor ....... 576
39.5.5.4. Ciliary Neurotrophic Factor ....... 576
39.5.5.5. Glial Derived Neurotrophic
Factor ............................ 576
39.5.6. Antiglutamatergic Agents .................... 577
39.5.6.1. Gabapentin ........................ 577
39.5.6.2. Topiramate ........................ 577
39.5.6.3. Lamotrigine ....................... 577
39.5.6.4. Ceftriaxone ....................... 577
39.5.6.5. Talampanel ........................ 577
39.5.6.6. Remacemide ........................ 577
39.5.7. Stem Cell Transplant Therapy ................ 577
39.5.7.1. Stem Cell Therapy and Parkinson's
Disease ........................... 577
39.5.7.2. Stem Cell Therapy and Huntington's
Disease ........................... 578
39.5.7.3. Stem Cell Therapy and Amyotrophic
Lateral Sclerosis ................. 578
39.5.8. Others ...................................... 578
39.5.8.1. Amyotrophic Lateral Sclerosis ..... 578
39.5.8.2. Alzheimer's Disease ............... 579
39.5.8.3. Huntington's Disease .............. 579
39.5.8.4. Parkinson's Disease ............... 580
Summary ................................................... 580
Review Questions/Problems ................................. 580
References ................................................ 581
40. Multiple Sclerosis ........................................ 589
M.Patricia Leuschen, Kathleen M.Healey, and Mary L.Filipi
40.1. Introduction ........................................ 589
40.1.1. Therapuetic Options and Disease
Definitions ................................. 589
40.1.2. Diagnosis and Disease Activity Measures ..... 590
40.1.3. Emerging Immune Modulators .................. 590
40.2. Historical Therapies for MS ......................... 591
40.2.1. Hypothetical Benefits Without Improved
Clinical Outcomes ........................... 591
40.2.1.1. Interferon γ (IFNγ) ............... 591
40.2.1.2. Histamine ......................... 591
40.2.1.3. From Placebos to Bee Stings ....... 591
40.2.2. Beneficial Immune Therapies: Use of
Steroids for Acute Episodes RR-MS ........... 592
40.3. Immunotherapies for RR-MS ........................... 592
40.3.1. FDA Approval of IFNβ-la, IFNp-lβ, and
Glatiramer Acetate for RR-MS ................ 592
40.3.1.1. FDA Trials and Their Outcome
Measures .......................... 592
40.3.1.2. Side Effects and Compliance ....... 593
40.3.1.3. MRI and Bioimaging to Evaluate
Clinical Efficacy ................. 593
40.3.1.4. Clinical Responses for SP-MS
and PP-MS ......................... 594
40.3.2. EAE Animal Models for MS Therapy
Development ................................. 594
40.3.3. Failed Clinical Trials ...................... 594
40.3.3.1. Tysabri (Natalizumab) ..................... 594
40.4. FDA Approved Therapies for MS ....................... 595
40.4.1. IFNP-la, (Avonex) ........................... 595
40.4.1.1. Nomenclature, Approved Dosing
Format, and Dosing Schedule ....... 595
40.4.1.2. Adverse Effects of IFN β-la
(Avonex) .......................... 595
40.4.1.3. Post Approval Efficacy ............ 595
40.4.2. IFN p-lb (Betaseron) ........................ 595
40.4.2.1. Nomenclature, Approved Dosing
Format, and Dosing Schedule ....... 595
40.4.2.2. Adverse Effects of Betaseron
(IFN-β-lb) ........................ 595
40.4.2.3. Mechanism of Action ............... 596
40.4.3. IFNp-la (Rebif) ............................. 596
40.4.3.1. Nomenclature, Approved Dosing
Format, and Dosing Schedule ....... 596
40.4.3.2. Adverse Effects of Rebif
(IFN-β-la) ........................ 596
40.4.3.3. Efficacy .......................... 596
40.4.4. Glatiramer Acetate (Copaxone) ............... 596
40.4.4.1. Nomenclature, Approved Dosing
Format, and Dosing Schedule ....... 596
40.4.4.2. Side Effects of Glatiramer
Acetate ........................... 596
40.4.4.3. Mechanism of Action and
Efficacy .......................... 596
40.5. Therapies Approved for RR-MS ........................ 597
40.5.1. Glatiramer Acetate Versus IFNβ-la (IM)
and IFNP-lβ ................................. 597
40.5.2. IFNβ-la (IM) and IFNβ-lb .................... 597
40.5.3. IFNβ-la Subcutaneous Versus IFNβ-la IM ...... 597
40.5.4. Glatiramer Acetate Versus IFNp-la
Subcutaneous, IFNβ-la IM and IFNβ-lb ........ 597
40.6. FDA Approved Therapies for Other Forms of MS ........ 597
40.6.1. Mitoxantrone (Novantron) .................... 597
40.7. Promising Areas for a New Generation of MS
Therapies ........................................... 597
40.7.1. Oral Therapy for MS ......................... 598
40.7.2. Immunosuppressant Chemotherapies and
Stem Cell Transplantation for MS ............ 598
Summary ................................................... 598
Review Questions/Problems ................................. 598
References ................................................ 599
41. HIV-Associated Dementia ................................... 605
Miguel G.Madariaga and Susan Swindells
41.1. Introduction ........................................ 605
41.1.1. Overview of HIV-Related Brain Disease ....... 605
41.1.2. Nomenclature ................................ 605
41.1.3. Natural History of HAD ...................... 605
41.2. Diagnosis ........................................... 606
41.2.1. Clinical Findings ........................... 606
41.2.2. Diagnostic Studies .......................... 606
41.2.2.1. Neuropsychological Testing ........ 606
41.2.2.2. Neuroimaging and Evoked
Potentials ........................ 607
41.2.2.3. CSF Studies ....................... 607
41.2.2.4. Histopathology .................... 607
41.3. Antiretroviral Therapy .............................. 608
41.3.1. Antiretroviral Classes ...................... 608
41.3.2. Initiating Antiretroviral Therapy: When
and What to Start ........................... 609
41.3.3. Antiretroviral Treatment Failure ............ 610
41.3.4. Importance of CNS Penetration in the
Treatment of HAD ............................ 610
41.3.5. Role of Specific Antiretroviral Agents
in the Treatment of HAD ..................... 611
41.4. Adverse Neurologic Effects of Antiretroviral
Agents .............................................. 611
41.4.1. Pharmacological Interactions Between
Antiretrovirals and Other Medications
with Activity in the Central Nervous
System ...................................... 612
41.5. Adjuvant Pharmacological Therapy for HAD ............ 612
41.5.1. CPI/1189 .................................... 612
41.5.2. Lexipafant .................................. 612
41.5.3. Memantine ................................... 612
41.5.4. Minocycline ................................. 613
41.5.5. Nimodipine .................................. 613
41.5.6. OPC-14117 ................................... 613
41.5.7. Peptide T ................................... 613
41.5.8. Selegiline .................................. 614
41.6. Additional Management Considerations ................ 614
41.6.1. Importance of Adherence to
Antiretroviral Therapy ...................... 614
41.6.2. Supportive Care ............................. 614
Summary ................................................... 615
Review Questions/Problems ................................. 615
References ................................................ 616
42. Immunotherapy ............................................. 621
Jonathan Kipnis
42.1. Introduction ........................................ 621
42.2. Immune Modulation in Neurodegenerative
Disorders and Neural Injuries ....................... 621
42.2.1. Corticosteroids for Glaucoma and
Spinal Cord Injury .......................... 622
42.2.2. Cyclosporine A and Neurodegenerative
Disorders ................................... 622
42.3. Immunomodulatory Therapeutics ....................... 623
42.3.1. T Cell Vaccination .......................... 623
42.3.2. Naturally Occurring CD4+ CD25+
Regulatory T Cells .......................... 623
42.3.3. Induction of Regulatory T Cells by
Mucosal Immunization ........................ 623
42.3.4. Copaxone .................................... 624
42.4. Vaccination for Neurodegenerative Disorders ......... 624
42.4.1. Harnessing Humoral Immune Responses
for Treatments of Spinal Cord Injuries
and Alzheimer's Disease ..................... 624
42.4.2. Innate and Adaptive Immunity ................ 625
Summary ................................................... 626
Review Questions/Problems ................................. 626
References ................................................ 627
43. Alzheimer's Disease ....................................... 631
Dave Morgan and Marcia N.Gordon
43.1. Introduction ........................................ 631
43.2. Early Studies ....................................... 633
43.3. Clinical Trial Experience with AB Vaccination ....... 634
43.4. Other Forms of Active Immunization .................. 635
43.5. Passive Immunization ................................ 636
43.6. Circulating Antibodies .............................. 636
Summary ................................................... 637
Review Questions/Problems ................................. 637
References ................................................ 638
44. Parkinson's Disease and Amyotrophic Lateral Sclerosis ..... 641
R.Lee Mosley, Ashley Reynolds, David K.Stone, and
Howard E.Gendelman
44.1. Introduction ........................................ 641
44.2. Protein Misfolding and Modifications ................ 643
44.2.1. α-Synuclein and SOD 1 Biology and
Biochemistry ................................ 643
44.2.2. Protein Nitration ........................... 643
44.3. Microglial Inflammatory Responses and Therapies ..... 643
44.3.1. Innate Immunity and Disease ................. 643
44.3.2. Oxidative Stress ............................ 644
44.3.2.1. DNA Modifications ................. 646
44.3.2.2. Lipid Peroxidation ................ 646
44.3.2.3. Glutathione ....................... 647
44.3.3. Modulation of Innate Immunity as
Therapeutic Targets ......................... 647
44.3.3.1. PPAR-γ ............................ 647
44.3.3.2. Minocycline and Modulators of
Microglial Activation ............. 647
44.4. Adaptive Immunity ................................... 648
44.4.1. Cell-Mediated Immunity ...................... 648
44.4.2. Humoral Immunity ............................ 649
44.5. Therapeutic Immunoregulation ........................ 650
44.5.1. Cell-Mediated Immunomodulation .............. 650
44.5.2. Modulation of Humoral Immunity .............. 651
44.5.3. Other Vaccine Strategies .................... 651
44.6. Neuroprotective Strategies .......................... 652
44.6.1. Growth Factors .............................. 652
44.6.2. Neuroprotectants ............................ 652
44.7. Genetics and Immunity ............................... 652
Summary ................................................... 653
Review Questions/Problems ................................. 653
References ................................................ 655
45. Protective and Regenerative Autoimmunity in CNS Injury .... 661
Jonathan Kipnis and Michal Schwartz
45.1. Introduction ........................................ 661
45.1.1. Inflammation—A Local Response in Acute
CNS Insults: Is It Always Bad? .............. 661
45.1.2. Role of Innate Immunity in CNS Repair ....... 662
45.1.3. Lessons from Peripheral Nervous
System—Wallerian Degeneration: Is It
Needed for Repair? .......................... 662
45.1.4. Macrophages/Microglia in CNS Repair ......... 663
45.1.4.1. The Rationale for Macrophage
Therapy and Its Preclinical
Characteristics ................... 664
45.2. Adaptive Immunity Is Needed to Control Local
Innate Response in the CNS .......................... 664
45.2.1. Is Self and Non-Self Discrimination
Needed? ..................................... 664
45.2.2. Autoimmune T Cells Protect Neurons from
Degeneration ................................ 665
45.2.3. The Mechanism Underlying Protective
Autoimmunity ................................ 667
45.2.4. The Missing Link—Adaptive Immunity
Controls Microglia Phenotype Needed
for Survival, Regrowth, and Renewal ......... 668
45.3. Development of Therapeutic Vaccinations ............. 669
45.3.1. Immune-Based Vaccination for
Neurodegenerative Diseases .................. 669
45.3.1.1. Copolymer-1
(Glatiramer acetate, CA) ........... 669
45.3.1.2. Lymphopenia ....................... 669
45.3.1.3. Attenuation of Regulatory T
Cell Network ...................... 670
Summary ................................................... 670
Review Questions/Problems ................................. 670
References ................................................ 671
46. Adjuvants ................................................. 679
Sam Sanderson
46.1. Introduction ........................................ 679
46.2. General Adjuvants: Vehicles and Immunomodulators .... 679
46.3. Present-Day Adjuvants in Human and Animal
Applications: General Mechanism of Action ........... 680
46.4. Molecular Adjuvants ................................. 680
46.4.1. Definition .................................. 680
46.4.2. Complement .................................. 680
46.4.3. Complement-Derived Molecular Adjuvants ...... 681
46.4.4. The Anaphylatoxins .......................... 681
46.4.5. Immunostimulatory and Inflammatory
Properties of C5a ........................... 681
46.4.6. C5a: Structure-Function Considerations ...... 682
46.4.7. Conformationally Restricted Analogues
of C5a65-74................................... 682
46.4.8. YSFKPMPLaR as a Molecular Adjuvant .......... 683
46.4.8.1. Generation of Ag-Specific
Antibody Responses ................ 684
46.4.8.2. Generation of Ag-Specific
Cell-Mediated Responses ........... 684
46.4.9. Improved Molecular Adjuvant Design:
N-Methylation of Backbone Amides ............ 686
46.5. Advantages of Molecular Adjuvant-Containing
Vaccines ............................................ 686
Summary ................................................... 686
Review Questions/Problems ................................. 687
References ................................................ 687
47. Polymer Nanomaterials ..................................... 691
Alexander V.Kabanov and Elena V.Batrakova
47.1. Introduction ........................................ 691
47.2. History and Principles of Drug Delivery Using
Polymers ............................................ 691
47.3. Nanocarriers for Drug Delivery ...................... 692
47.3.1. Types of Nanocarriers for Drug Delivery
to the Brain ................................ 693
47.3.2. Cell-Mediated Delivery of Nanocarriers
to the Brain ................................ 696
47.3.3. Permeability Enhancers for CNS Drug
Delivery ................................... 697
47.3.4. Chemical Modification of Polypeptides
with Fatty Acids and Amphiphilic
Block Copolymers ............................ 699
Summary ................................................... 701
Review Questions/Problems ................................. 701
References ................................................ 702
48. Gene Therapy and Vaccination .............................. 709
William J.Bowers, Michelle C.Janelsins,
and Howard J.Federoff
48.1. Introduction ........................................ 709
48.2. Vector Selection Rationale .......................... 709
48.3. Gene Transfer Platforms ............................. 710
48.3.1. Nonviral Gene Transfer ...................... 710
48.3.2. Adenovirus Vectors .......................... 711
48.3.3. Adeno-Associated Virus Vectors .............. 711
48.3.4. Lentivirus Vectors .......................... 712
48.3.5. Herpes Simplex Virus Vectors ................ 713
48.3.5.1. HSV Recombinant Vectors ........... 713
48.3.5.2. HSV Amplicon Vectors .............. 714
48.4. Neuroimmunotherapy .................................. 715
48.4.1. Immunotherapeutic Approaches to Treating
Neurodegenerative Diseases .................. 716
48.4.2. Single Chain Antibodies as Passive
Immunotherapeutics .......................... 716
48.4.3. Active Vaccination .......................... 717
48.4.4. Immune Shaping: Thl and Th2 Responses
and Antibody Isotypes ....................... 717
48.4.5. Evaluating an Appropriate Active Vaccine
Response for Alzheimer's Disease ............ 718
48.5. Future Outlook ...................................... 718
Summary ................................................... 718
Review Questions/Problems ................................. 719
References ................................................ 719
49. Proteomics and Genomics ................................... 725
Wojciech Rozek and Panel S. Ciborowski
49.1. Introduction ........................................ 725
49.2. Proteomics and Genomics—Technologies for Global
Oversight of Complex Biological Systems ............. 725
49.3. Proteomics Technologies ............................. 727
49.4. Biomarkers .......................................... 729
49.5. Proteomics in Biomarker Discovery ................... 729
49.6. Proteomics of CSF ................................... 730
49.7. Neuroproteomics ..................................... 731
49.8. Functional Genomics ................................. 732
49.9. Gene Arrays ......................................... 733
49.10.Genomics in Neuroinflammation ....................... 733
49.11.Protein Microarrays ................................. 734
49.12.Proteomics and Tissue Profiling ..................... 735
49.13.Bioinformatics and Information Networks ............. 735
Summary ................................................... 736
Review Questions/Problems ................................. 736
References ................................................ 737
50. Neuroimaging .............................................. 743
Michael D.Boska and Matthew L.White
50.1. Introduction ........................................ 743
50.2. Principles of Imaging ............................... 743
50.2.1. Basic Principles of MRI ..................... 743
50.2.1.1. Signal Source ..................... 743
50.2.1.2. Precession and the Larmor
Equation .......................... 744
50.2.1.3. Resonance ......................... 744
50.2.1.4. Signal Detection and Time
Evolution ......................... 744
50.2.1.5. Magnetic Field Gradient Used
to Generate MRI ................... 745
50.2.1.6. Fourier Transform: Frequency
Analysis of the Time Domain MR
Signal ............................ 745
50.2.1.7. Spin Echo ......................... 745
50.2.1.8. Spin-Echo Magnetic Resonance
Imaging (MRI) ..................... 746
50.2.2. Modification of Signal Intensity ............ 746
50.2.2.1. Magnetic Relaxation, Tl and T2 .... 747
50.2.2.2. Diffusion ......................... 748
50.2.2.3. Magnetization Transfer ............ 750
50.2.2.4. Perfusion ......................... 750
50.2.2.5. Relaxometry, Quantitative DWI
and Quantitative MT ............... 752
50.2.3. Magnetic Resonance Spectroscopy and
Spectroscopic Imaging ....................... 752
50.2.4. Computed Tomography Methods, X-Ray
Computed Tomography, Single Photon
Emission Computed Tomography and
Positron Emission Tomography ................ 753
50.3. Information Content ................................. 754
50.3.1. Magnetic Resonance Techniques ............... 754
50.3.1.1. T,, T„ and Proton Density
Weighted MRI ....................... 754
50.3.1.2. Diffusion Weighted Imaging
(DWI) ............................. 755
50.3.1.3. Diffusion Tensor Imaging .......... 755
50.3.1.4. Magnetization Transfer (MRI) ...... 756
50.3.1.5. Perfusion MRI ..................... 756
50.3.1.6. 'H MRSI ........................... 756
50.3.2. Computed Tomography ......................... 757
50.3.3. Single Photon Emission Computed
Tomography .................................. 758
50.3.4. Positron Emission Tomography ................ 759
Summary ................................................... 760
Review Questions/Problems ................................. 760
References ................................................ 761
Glossary ...................................................... 765
Index ......................................................... 793
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