Exploring Rosiglitazone’s Potential to Treat Alzheimer’s Disease through the Modulation of Brain-Derived Neurotrophic Factor

SIMPLE SUMMARY: This review focuses on rosiglitazone, a medication used to treat diabetes. Rosiglitazone lowers blood sugar levels by helping the body use insulin more efficiently. Individuals with diabetes have a higher risk of developing Alzheimer’s disease, a complex memory-loss disorder affecting millions of individuals globally. Although scientists do not know why, diabetes may interfere with the ability of the brain to respond to insulin. Diabetes and Alzheimer’s disease have a lot in common when it comes to symptoms, brain changes and disease progression. As a result, researchers are investigating the potential of anti-diabetic drugs, such as rosiglitazone, to treat Alzheimer’s disease. Although the results in human clinical trials have not been promising, rosiglitazone provided significant improvements in cellular and animal models of Alzheimer’s disease, with even more promising results observed when rosiglitazone was formulated with nanosized particles that can assist with drug delivery. This review proposes that rosiglitazone may provide these benefits by modulating brain-derived neurotrophic factor, a critical protein for brain and metabolic health. ABSTRACT: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that debilitates over 55 million individuals worldwide. Currently, treatments manage and alleviate its symptoms; however, there is still a need to find a therapy that prevents or halts disease progression. Since AD has been labeled as “type 3 diabetes” due to its similarity in pathological hallmarks, molecular pathways, and comorbidity with type 2 diabetes mellitus (T2DM), there is growing interest in using anti-diabetic drugs for its treatment. Rosiglitazone (RSG) is a peroxisome proliferator-activated receptor-gamma agonist that reduces hyperglycemia and hyperinsulinemia and improves insulin signaling. In cellular and rodent models of T2DM-associated cognitive decline and AD, RSG has been reported to improve cognitive impairment and reverse AD-like pathology; however, results from human clinical trials remain consistently unsuccessful. RSG has also been reported to modulate the expression of brain-derived neurotrophic factor (BDNF), a protein that regulates neuroplasticity and energy homeostasis and is implicated in both AD and T2DM. The present review investigates RSG’s limitations and potential therapeutic benefits in pre-clinical models of AD through its modulation of BDNF expression.