Brain Insulin Resistance, Nitric Oxide and Alzheimer’s Disease Pathology

Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disease characterized by progressive pathological changes and functional and cognitive impairments. Brain insulin resistance appears to contribute significantly to the pathology and cognitive deficits among several pathological mechanisms. Brain insulin resistance has been demonstrated in animal models of AD and postmortem human brain tissue from patients with AD dementia. Studies conducted in AD models and humans suggest attenuating brain insulin resistance by agents such as glucagon-like peptide1 (GLP-1) analogs and small molecule drug candidate PTI-125 reduces many AD pathologic features and symptoms. Insulin affects NO levels by activating endothelial and neuronal nitric oxide synthase (eNOS, nNOS), and systemic insulin resistance has been linked to reduced nitric oxide (NO) bioavailability. Increasing NO availability reduces systemic insulin resistance, and the insulin signaling pathway is associated with the activation of eNOS, implying a causal relationship. This chapter explores this relationship and the role of impaired NO availability in brain insulin resistance in AD dementia.