This book presents the reader with an understanding of the role played by matrix metalloproteinases (MMPs) in the normal and diseased central nervous system (CNS). These enzymes may be important to brain development, and may also contribute to tissue destruction, which is observed with inflammatory and degenerative conditions of the brain. The book provides a background on the biology of MMPs, and on the stimuli and conditions that are linked to an increase in their production and activity. It describes the targets of MMPs, which include matrix proteins such as collagen, soluble cytokines and chemokines, and cell surface receptors. Studies implicating MMPs in neuronal process outgrowth and cell migration in CNS development are covered. The book also touches on studies suggesting that, in certain situations, dysregulated MMP activity and/or production may be critical to blood–brain barrier breakdown and neuronal damage.
Author(s): Katherine Conant, Paul E Gottschall
Edition: illustrated edition
Publisher: Imperial College Press
Year: 2005
Language: English
Commentary: 41812
Pages: 346
CONTENTS......Page 6
Foreword......Page 8
I. A Brief Overview......Page 10
1. Introduction......Page 12
2. The MMP Family......Page 13
3. Regulation of MMP Activity......Page 15
4. Endogenous Inhibitors of Metalloproteinases......Page 17
6. ECM Targets in the CNS......Page 19
8. Growth Factor Liberation from ECM “Stores”......Page 20
11. Conclusion......Page 21
References......Page 22
II. Regulation of MMP Expression......Page 26
1. Introduction......Page 28
2. Stimuli Triggering Alterations in MMP Gene Expression......Page 29
4. Neurotransmitters......Page 30
6. Physical and Biochemical Stress......Page 31
8. Feedback Control......Page 32
9.1. The MAPK pathway......Page 33
9.3. The ‘JAK/STAT’ pathway......Page 34
9.5. The Smad pathway......Page 35
9.7. Pathways operating in the nervous system......Page 36
10.1. Constitutive and inducible transcription factors......Page 37
10.2. Orchestrating multigene responses......Page 38
10.3. AP-1 binding sites and related elements......Page 39
10.4. Other promoter elements......Page 41
11.1. The MMP-2 gene......Page 42
11.3. The MMP-14 gene......Page 43
12. Regulation of ADAMs Family Gene Expression......Page 44
13. Regulation of TIMP Gene Expression......Page 45
15. Regulation of TIMPs Independent of MMP Inhibitory Functions......Page 47
16. Post-Transcriptional Regulation of MMP Expression......Page 48
17. Regulation of MMP Gene Expression in the Healthy Nervous System......Page 49
18. Neuronal Expression......Page 50
20. Microglial Expression......Page 51
22. Oligodendrocyte and Schwann Cell Expression......Page 52
23. Expression of TIMPs in the Nervous System......Page 53
24. Expression in Nervous System Development and Plasticity......Page 54
26. Regulation in Nervous System Malignancies......Page 55
27. Regulation in Nervous System Injury......Page 57
28. Genetic Polymorphisms and MMP Expression......Page 60
References......Page 62
1. Introduction......Page 76
2. Cysteine Switch Mechanism......Page 77
3. Modification of MMPs by S-Nitrosylation......Page 78
5. NO-Induced Subsequent Oxidation......Page 79
6. Peptide Mass Fingerprinting Analysis of Cysteine Residue Post-Translational Modifications......Page 80
8. MMPs in Neurological Diseases......Page 84
9. Neuronal NOS-Associated Activation of MMP During Stroke......Page 87
10. Exogenous NO-Activated MMP-9 Induces Neuronal Apoptosis in Cerebrocortical Cultures......Page 88
12. Summary......Page 89
References......Page 90
III. MMP Function......Page 94
1. Introduction......Page 96
2. Substrates in the Basal Lamina (Basement Membrane)......Page 98
3. Collagen Type IV......Page 99
5. Perlecan and Other Heparan Sulfate Proteoglycans (HSPG)......Page 100
6. Entactins (Nidogens)......Page 101
7. Substrates in the Neuropil and Perineuronal Nets......Page 102
9. Hyalectans (Lecticans, Aggregating PGs)......Page 103
10. Expression, Localisation and Molecular/Cellular Interactions......Page 106
11. Proteolytic Processing of the Hyalectans......Page 108
12. Methods of Identifying Metalloproteinase Activity In Vivo......Page 111
15. Expression, Localisation and Molecular/Cellular Interactions......Page 113
18.1. Dystroglycan......Page 115
19.2. Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)......Page 116
20.1. -amyloid precursor protein (APP)......Page 117
20.4. Myelin basic protein......Page 118
References......Page 119
1. Signalling Related to Proteolysis of Matrix and Matrix-Like Proteins......Page 128
1.1. Anoikis, or cell death by loss of anchorage, involves changes in intracellular signalling and may be stimulated by mechanisms including proteolysis of either matrix or cadherins......Page 129
1.2. Proteolysis may also lead to the generation of matrix-derived fragments, or matrikines, that can stimulate changes in cell signalling......Page 131
1.4. Proteolysis of matrix-like proteins......Page 133
2.1. Cleavage of host proteins by pathogen derived MPs......Page 134
2.3. MMPs may process soluble molecules that influence neuronal structure, survival or migration......Page 135
2.4. MMPs may process soluble molecules involved in pain......Page 136
2.5. MMPs may process molecules involved in neurodegenerative disease......Page 137
3.1. MMPs can act on molecules that play a role in CNS inflammation, such as ICAM......Page 138
3.2. Effects on other adhesion molecules......Page 139
3.3. Cleavage of Fas ligand......Page 140
3.4. MMPs act on receptors important to neuronal migration, structure, and/or survival......Page 141
4.1. Like a number of snake venom MPs, MMPs may bind to integrins......Page 143
4.2. Interactions between MMPs and cell surface receptors may be relevant to development and disease......Page 149
5. Miscellaneous......Page 150
References......Page 151
IV. MMPs and TIMPs in Development......Page 160
1. Introduction......Page 162
2. Metalloproteinase Expression in the Developing Nervous System......Page 163
3. Analysis of Metalloproteinase Function......Page 165
4. Neurogenesis......Page 167
5. Neuronal Survival......Page 171
6. Neuronal Migration......Page 174
7. Axon Extension and Guidance......Page 177
8. Mechanisms of Metalloproteinase Function......Page 187
9. Dendrite Development......Page 190
References......Page 191
1. Regulation of Myelin Formation......Page 198
2.2. MMP-12 and its role in OL biology......Page 200
2.3. MMP-9 and -12 in developmental myelination......Page 202
3.1. MMP-9 has a role in the remyelination process......Page 203
3.2. MMP-9 regulates remyelination in part by processing the inhibitory NG2 proteoglycan......Page 205
4. MMPs in Demyelinating Diseases......Page 206
5. MMPs: Detrimental and Bene.cial After Injury......Page 208
6. Conclusion......Page 209
References......Page 210
1. Developmental Regulation of TIMPs......Page 216
2. TIMPs in the Mature Nervous System......Page 219
3. TIMPs in Neuropathology......Page 222
References......Page 226
V. MMPs and TIMPs in Disease......Page 234
1. Introduction......Page 236
2. Matrix Metalloproteinase Biology......Page 237
3. MMPs and Neuroinflammation......Page 238
4. MMPs and the Neurovascular Unit......Page 242
5. Cell Death Following Cerebral Ischemia......Page 243
6. MMP Modulation of Neuronal Death......Page 245
7. TIMP Regulation of Neuronal Death......Page 248
References......Page 252
1. The Atherosclerotic Plaque: Characteristics and Evolution......Page 258
2. MMPs in Atherosclerosis......Page 259
3. Regulation of MMPs in Atherosclerosis......Page 260
4. Functions of MMPs in Atherosclerosis......Page 262
5. MMPs and Aneurysm Degeneration......Page 264
6. Conclusion......Page 266
References......Page 267
1. Introduction......Page 272
2. The ECM of the Brain......Page 273
3. Matrix Metalloproteinases......Page 274
4. MMP Expression in Gliomas......Page 275
5. Regulation of MMPs......Page 276
6. Therapy......Page 279
References......Page 281
1. Introduction......Page 288
2. Alzheimer’s Disease and Other Dementias......Page 289
4. Expression of Matrix Metalloproteinases in Alzheimer’s Disease and Related Disorders......Page 290
6. The ADAMs Family in Alzheimer’s Disease......Page 293
7. The TIMPs in Alzheimer’s Disease......Page 295
8. Regulation of the MMPs in Alzheimer’s Disease......Page 296
10. Relationships with A Species......Page 298
11. Effects of MMPs on Neuronal Biology......Page 300
12. The Blood-Brain Barrier and MMPs in Alzheimer’s Disease......Page 301
13. Genetic Associations between MMPs and Related Proteins and Alzheimer’s Disease......Page 302
14. Other Neurodegenerative Diseases......Page 303
17. Amyotrophic Lateral Sclerosis......Page 304
18. Trinucleotide Repeat Disorders......Page 305
19. Therapeutic Implications......Page 306
References......Page 307
1. Introduction......Page 320
2. Properties of the TIMPs......Page 321
3. Anatomical Distribution of the TIMPs......Page 323
4.1. Demyelinating disorders......Page 327
4.2. Cerebral ischemia......Page 330
4.3. Infectious disorders......Page 331
5. TIMPs and Viral Infections......Page 332
6. TIMPs and Bacterial Infections......Page 335
7. Conclusion......Page 336
References......Page 337
Index......Page 342
