Diabetes, Insulin and Alzheimer's Disease (eBook)

Forword 6
Acknowledgments 7
Contents 8
List of contributors 10
Insulin Action in the Brain and the Pathogenesis of Alzheimer’s Disease 13
1 The Insulin Signaling System 13
2 Linking the Receptor to the Insulin and IGF-1 Signaling Pathways 16
3 Regulation of the IRS and IGF-1 Receptors in Physiology and Pathophysiology 17
4 Creation and Characterization of the Brain IR Knockout Mouse 18
5 Impairment of insulin Signaling in Brain is Linked to Neurodegenerative Disease 20
6 Insulin-degrading Enzyme in Pathogenesis of Alzheimer’s Disease and Metabolic Diseases 22
7 Insulin, Diabetes, and Brain Cholesterol Metabolism 24
References 26
The Brain-insulin Connection, Metabolic Diseases and Related Pathologies 33
1 Introduction 34
2 Central Interplay of Insulin with Hormones, Neuropeptides and Neurotransmitters 35
3 Mechanisms of Action 36
4 Metabolic, Mood and Neurodegenerative Pathologies 38
+ 43
5 Current treatment trends 44
6 Conclusion 45
References 46
Insulin-Mediated Neuroplasticity in the Central Nervous System 55
1 Introduction 56
2 Morphological Plasticity 56
3 Oxidative Stress 57
4 Hypothalamic-Pituitary-Adrenal Axis Dysfunction 58
5 Insulin and the Glutamate System 59
6 Leptin 60
7 Insulin 61
8 Conclusions 62
References 63
Stress Hormones and Neuroplasticity in the Diabetic Brain 69
1 Introduction 69
2 Deficits in Hippocampal Structure and Function in Rodent Models of Diabetes 70
3 Diabetes and the HPA Axis 72
4 Effect of Diabetes on Hippocampal Structure and Function: A Role for Glucocorticoids 73
5 Diabetes and Elevated Glucocorticoids in Human Cognition 74
6 Interventions that Attenuate Diabetes also Reverse Central Diabetic Encephalopathy 75
7 Brain-derived Neurotrophic Factor and Diabetes 76
8 Stress, Diabetes, and AD Pathology 77
9 Epidemiology of Diabetes, Stress, and AD in Humans 77
10 Summary and Conclusion 78
References 79
Diabetes and the Brain – An Epidemiologic Perspective 84
1 Brief Description of Evidence Linking Diabetes to Late-age Cognitive Disorders 84
2 Integrated Community-Based Studies of Diabetes and the Brain 85
3 Cognitive Function 86
4 Brain Structure 87
References 89
Cognition in Type 2 Diabetes: Brain Imaging Correlates and Vascular and Metabolic Risk Factors 92
1 Introduction 93
2 Defining Cognitive Dysfunction 93
3 Defining Diabetes 94
4 Cognition and Dementia in DM2 and Pre-diabetic Stages 94
5 Brain Imaging in DM2 96
6 Risk Factors for Impaired Cognition and Brain Imaging Abnormalities in DM2 96
7 Conclusion 97
References 97
The Relationship Between the Continuum of Elevated Adiposity, Hyperinsulinemia, and Type 2 Diabetes and Late- onset Alzheimer’s Disease: An Epidemiological Perspective 100
1 Introduction 100
2 The Continuum of Adiposity, Hyperinsulinemia, and Type 2 Diabetes 101
2.1 Potential Mechanisms Relating the Continuum of Elevated Adiposity, Hyperinsulinemia, and Type 2 Diabetes with LOAD 104
2.2 Cerebrovascular Mechanisms. Brain Infarcts 104
2.3 White Matter Disease 105
2.4 Hyperinsulinemia and Beta Amyloid Clearance 105
3 Summary of Prospective Epidemiological Studies Linking Adiposity, Hyperinsulinemia, and Diabetes to AD 3.1 Adiposity 106
3.2 Hyperinsulinemia 107
3.3 Type 2 Diabetes 108
3.4 Metabolic Syndrome 109
4 Implications for the Prevention and Treatment of AD 109
References 111
The Role of Insulin Dysregulation in Aging and Alzheimer’s Disease 119
1 Insulin and the Brain 119
2 Insulin Resistance and AD 121
2.1 Insulin Abnormalities and AD Pathology 121
2.2 Insulin Resistance and Vascular Dysfunction 124
3 Therapeutic Implications of Insulin Resistance as a Pathogenetic Mechanism in AD 3.1 Pharmacologic Insulin Sensitization 125
4 Intranasal Insulin 127
4.1 Intranasal Pathways to the CNS 128
4.2 Intranasal Drug Administration 128
4.3 Intranasal Insulin Effects in the CNS 129
5 Conclusions 132
References 132
Is Alzheimer’s a Disorder of Ageing and Why Don’t Mice get it? The Centrality of Insulin Signalling to Alzheimer’s Disease Pathology 138
1 Introduction 138
2 The Role of GSK-3 in AD Pathology 140
3 Genetic and Environmental Risk Factors Converge on Insulin Signalling 145
4 Is AD a Disorder of Ageing? 146
5 Why Don’t Mice get AD? 148
6 Insulin Signalling and Cellular and Animal Models of AD 150
7 Conclusions and Way Forward 152
References 153
PKC and Insulin Pathways in Memory Storage: Targets for Synaptogenesis, Anti- apoptosis, and the Treatment of AD 162
1 Introduction 163
2 Insulin, Insulin-like Growth Factor, and PKC Signaling 164
3 Synaptic Transmission and Synaptogenesis 165
4 PKC, APP, and Synaptogenesis 167
5 Neuronal Survival, Neurogenesis, and Anti-apoptosis 171
6 Insulin, PKC, and Learning and Memory 171
7 Insulin Pathways, Insulysin, PKC, and AD 173
8 Treatment of AD via Targeting the PKC and Insulin Signaling Pathways 176
9 Concluding Remarks 180
References 180
Diet, Abeta Oligomers and Defective Insulin and Neurotrophic Factor Signaling in Alzheimer’s Disease 192
1 Introduction 193
2 AD Pathogenesis 193
3 Insulin Signaling and AD Pathogenesis 195
4 IRS-1 Defects in AD 196
5 IRS-1 Defects in Preclinical Models Relevant to AD 197
6 Western Diet Versus Omega 3 Fatty Acids 200
7 Curcumin 201
8 Omega-3 Protection in Humans 201
9 Clinical trials 202
10 Conclusions 202
References 203
Serum IGF-I, Life Style, and Risk of Alzheimer’s disease 209
1 Introduction 210
2 Neuroprotection by Brain- and Serum-derived IGF-I 210
3 Factors Influencing Serum IGF-I Levels 212
4 Influence of Environmental Factors on the Passage of Serum IGF- I into the Brain 213
5 Insulin, IGF-I and Late-onset AD 215
6 Conclusions 217
References 217
Index 222