[Frontiers in Bioscience E4, 1582-1605, January 1, 2012]

Therapeutic targets of brain insulin resistance in sporadic Alzheimer's disease

Suzanne M. de la Monte1

1Departments of Neurology, Neurosurgery, and Neuropathology, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Alzheimer's disease: a brain form of diabetes mellitus
4. Systemic disease factors contributing to brain insulin/IGF resistance and AD neurodegeneration
4.1. Contributions of obesity and T2DM to cognitive impairment and neurodegeneration
4.2. Pathological processes contributing to cognitive impairment and neurodegeneration in states of systemic insulin resistance.
4.2.1. Vascular factors
4.2.2. Neurotoxic lipids
4.2.3. Liver brain axis hypothesis
5. Central nervous system pathogenic factors mediating primary brain insulin/IGF resistance (type 3 diabetes)
5.1. Role of tau pathology in the pathogenesis of type 3 diabetes
5.2. Contributions of Amyloid-β neurotoxicity in type 3 diabetes
5.3. Stress factors in the pathogenesis of brain insulin resistance
5.4. Reverberating loop of neurodegeneration
6. Environmental/exposure factors potentially mediating brain insulin/IGF resistance and neurodegeneration
6.1. Environmental toxins/exposures as mediators of type 3 diabetes
7. Potential therapeutic targets for AD
7.1. Targeting insulin deficiency
7.1.1. Intranasal insulin therapy
7.1.2. Insulin stimulating/releasing hormones (incretins)
7.2. Targeting insulin resistance
7.2.1. Anti-hyperglycemic agents
7.2.2. Insulin sensitizers
7.3. Targeting tau pathology
7.4. Reducing amyloid burden to restore insulin responsiveness
7.5. Anti-oxidant and anti-inflammatory drugs
7.5.1. Non-steroidal anti-inflammatory drugs (NSAIDS)
7.5.2. Radical scavengers
7.5.3. Transition metal chelators
7.5.4. Polyphenols
8. Conclusions
9. Acknowledgements
10. References

1. ABSTRACT

Growing evidence supports roles for brain insulin and insulin-like growth factor (IGF) resistance and metabolic dysfunction in the pathogenesis of Alzheimer's disease (AD). Whether the underlying problem stems from a primary disorder of central nervous system (CNS) neurons and glia, or secondary effects of systemic diseases such as obesity, Type 2 diabetes, or metabolic syndrome, the end-results include impaired glucose utilization, mitochondrial dysfunction, increased oxidative stress, neuroinflammation, and the propagation of cascades that result in the accumulation of neurotoxic misfolded, aggregated, and ubiquitinated fibrillar proteins. This article reviews the roles of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism, and discusses therapeutic strategies and lifestyle approaches that could be used to prevent, delay the onset, or reduce the severity of AD. Finally, it is critical to recognize that AD is heterogeneous and has a clinical course that fully develops over a period of several decades. Therefore, early and multi-modal preventive and treatment approaches should be regarded as essential.