Pathobiology of Alzheimer's Disease (Neuroscience Perspectives)

Front Cover......Page 1
Pathobiology of Alzheimer\'s Disease......Page 4
Copyright Page......Page 5
Contents......Page 6
Contributors......Page 10
Series Preface......Page 12
Preface......Page 14
1.1 The Alzheimer century......Page 16
1.2 Early history of dementia and Alzheimer’s disease......Page 17
1.3 Alois Alzheimer and his disease......Page 19
1.4 Further progress with plaques and tangles......Page 20
References......Page 21
2.1 The anatomy of neurofibrillary degeneration......Page 24
2.2 The ultrastructure of neurofibrillary tangles......Page 27
2.3 Molecular analysis of the PHF core......Page 28
2.4 Development and application of quantitative methods for measuring PHF-bound tau......Page 33
2.5 Quantitative studies of tau protein in PHF preparations......Page 36
2.6 Phosphorylation of tau protein......Page 41
2.7 Immunohistochemical studies of altered tau processing in Alzheimer’s disease......Page 43
2.8 Aetiology of abnormal tau processing in Alzheimer’s disease – insights from other neurodegenerative disorders......Page 45
2.9 Conclusion......Page 47
References......Page 50
Summary......Page 56
3.1 Introduction......Page 57
3.2 Molecular components of the pathological signatures of Alzheimer’s disease......Page 59
3.3 Formation of neurofibrillary lesions from derivatized forms of CNS τ (PHFτ) in Alzheimer’s disease......Page 62
3.4 Kinases and phosphatases potentially involved in the conversion of normal CNS τ into PHFτ in Alzheimer’s disease......Page 65
3.5 Functional implications of neurofibraary lesions in Alzheimer’s disease......Page 66
References......Page 69
Summary......Page 74
4.2 Clinical and pathological features of Alzheimer’s disease......Page 75
4.3 Other cerebral amyloidoses......Page 76
4.5 Linkage to chromosome 21......Page 77
4.6 Exclusion of the APP gene......Page 78
4.7 Mutations in the APP gene......Page 79
4.8 Importance of APP mutations in Alzheimer’s disease......Page 84
4.9 Pathogenicity of the APP mutations......Page 85
4.10 Clinical and pathological features associated with APP mutations......Page 86
4.11 Linkage of AD to other loci......Page 88
References......Page 90
Summary......Page 94
5.3 APP expression in Down’s syndrome......Page 95
5.4 APP expression in response to activating factors......Page 96
5.5 Sequence elements of potential regulatory significance in the APP promoter......Page 97
5.6 Analysis of APP promoter regulation......Page 100
5.7 Conclusion......Page 108
Addendum......Page 110
References......Page 111
6.1 Introduction......Page 114
6.2 Protein kinase C and APP......Page 116
6.3 Regulation of APP processing by intracellular messengers......Page 120
6.4 Regulation of APP processing by calcium......Page 122
6.5 Regulation of APP processing in vivo......Page 124
6.6 Summary......Page 125
References......Page 126
7.1 Amyloid and Alzheimer’s disease......Page 130
7.2 Aβ deposition in Alzheimer’s disease......Page 131
7.3 The APP......Page 132
7.4 Genetic evidence for a causal role of amyloid deposition in Alzheimer’s disease......Page 134
7.5 APP processing......Page 136
7.6 Implications for future research on Alzheimer’s disease......Page 147
References......Page 154
8.1 Introduction......Page 160
8.2 Neurotoxicity of Aβ and related peptides......Page 161
8.3 Neurotoxicity of carboxyl terminal fragments of APP......Page 165
8.4 Neurotoxicity of abnormally metabolized APP fragments......Page 167
8.5 An alternative hypothesis for amyloid-associated neuronal death in AD......Page 175
8.6 Conclusion......Page 178
References......Page 179
9.1 Introduction......Page 182
9.2 Characterization and distribution of APP......Page 183
9.3 Potential physiological roles of APP......Page 188
9.4 Conclusions......Page 194
References......Page 195
10.1 Introduction......Page 198
10.2 Biology of APP and Aβ......Page 199
10.3 Animal models of AD......Page 201
References......Page 204
11.1 Introduction......Page 208
11.2 Clinical phenotype......Page 209
11.3 Plaques, tangles and Alzheimer’s disease......Page 215
11.4 Clinicopathological correlations in AD......Page 230
11.5 Conclusions......Page 232
References......Page 233
12.1 Apolipoprotein E......Page 240
12.2 ApoE and LDL receptor: a role in PNS regeneration and CNS reinnervation......Page 242
12.3 Synaptic remodelling and Alzheimer’s disease: a role for ApoE?......Page 246
12.4 Alzheimer’s disease and ApoE4......Page 250
12.5 ApoE4 and neuropathological features......Page 252
12.6 ApoE4 and cholinergic deficits......Page 254
References......Page 258
Index......Page 262
Color Plate Section......Page 272