Pathobiology of Alzheimer's Disease (Neuroscience Perspectives)

Neuroscience Perspectives provides multidisciplinary reviews of topics in one of the most diverse and rapidly advancing fields in the life sciences. Whether you are a new recruit to neuroscience, or an established expert, look to this series for 'one-stop' sources of the historical, physiological, pharmacological, biochemical, molecular biological and therapeutic aspects of chosen research areas. The last decade has seen tremendous advances in our understanding of the pathobiology of Alzheimer's disease. These will lead to the first generation of drugs aimed at prevention rather than cure. This book covers some of the most important and exciting of these advances, with chapters written by many of the leading researchers in the field. With genetic studies as a backbone to this volume many chapters are devoted to the function and regulation of amyloid b-protein precursor (APP) and apolipoprotein E (ApoE). Other chapters describe cell biological approaches helping to piece together the link between the genetic alterations and the phenotype we call Alzheimer's disease. Although APP and its proteolytic cleavage product, amyloid b-protein, do not answer all the questions, detailed research into this system has undoubtedly increased our knowledge of the pathobiology of AD and has lead to the identification of other risk factors. Understanding the role of ApoE in the pathology of Alzheimer's disease promises to open a whole new field in AD research. * * Reviews the current knowledge of the pathogenesis of Alzheimer's Disease from a clinical perspective to a genetic and cell biological perspective * A comprehensive description of the role of amyloid B-protein precursor in Alzheimer's disease. * Up-to-date research data * Clear illustrations complement the text 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 Annotation Neuroscience Perspectives provides multidisciplinary reviews of topics in one of the most diverse and rapidly advancing fields in the life sciences. Whether you are a new recruit to neuroscience, or an established expert, look to this series for 'one-stop' sources of the historical, physiological, pharmacological, biochemical, molecular biological and therapeutic aspects of chosen research areas. The last decade has seen tremendous advances in our understanding of the pathobiology of Alzheimer's disease. These will lead to the first generation of drugs aimed at prevention rather than cure. This book covers some of the most important and exciting of these advances, with chapters written by many of the leading researchers in the field. With genetic studies as a backbone to this volume many chapters are devoted to the function and regulation of amyloid b-protein precursor (APP) and apolipoprotein E (ApoE). Other chapters describe cell biological approaches helping to piece together the link between the genetic alterations and the phenotype we call Alzheimer's disease. Although APP and its proteolytic cleavage product, amyloid b-protein, do not answer all the questions, detailed research into this system has undoubtedly increased our knowledge of the pathobiology of AD and has lead to the identification of other risk factors. Understanding the role of ApoE in the pathology of Alzheimer's disease promises to open a whole new field in AD research. * * Reviews the current knowledge of the pathogenesis of Alzheimer's Disease from a clinical perspective to a genetic and cell biological perspective * A comprehensive description of the role of amyloid B-protein precursor in Alzheimer's disease. * Up-to-date research data * Clear illustrations complement the text Progress in understanding the biochemical, cellular and molecular genetic basis of Alzheimer's disease has been so rapid in recent years that it is almost impossible for texts such as this one to keep abreast of developments.