Insulin resistance: fueling oxidative stress and neurodegeneration

The growing prevalence of age-related neurodegenerative diseases is a consequence of population aging and demands urgent treatment strategies. This literature review aims to provide a comprehensive overview of the contribution of oxidative stress and insulin resistance in neurodegenerative diseases, specifically Alzheimer's disease (AD). In addition, current therapeutic approaches to treat oxidative stress and insulin resistance in this age-related neurodegenerative disease will be discussed. AD is the most prevalent form of neurodegenerative disease and is marked at early stages by oxidative stress and insulin resistance. Results indicate that insulin resistance may be central in generating oxidative stress and exacerbating AD hallmarks. In turn, insulin resistance can be influenced by other factors, including amyloid beta (Aβ), impaired biliverdin-reductase A (BVR-A) activity, and the gut microbiota. Defective insulin signaling in the brain comes with consequences ranging from declined cognitive functions, impaired autophagy, mitochondrial dysfunction, hyperphosphorylation of Tau, and increased Aβ production. Multiple therapeutic approaches that target oxidative stress or brain insulin resistance, such as antioxidant supplementation and anti-diabetic drugs, have mostly been inconclusive, except for intranasal insulin. Positive results have been obtained in clinical trials using nasal delivery devices to administer insulin; however, results are inconsistent across studies likely due to inconsistencies in the delivery method. Future investigations should focus on investigating the molecular link between oxidative stress, insulin resistance, and AD to address current knowledge gaps. Moreover, more focus should be given to optimizing the reliability and efficacy of nasal delivery devices before considering such an approach viable to treat neurodegenerative diseases.