Insulin Signaling in Alzheimer's Disease: Association with Brain Insulin Resistance

Insulin is an anabolic hormone involved in the regulation of several processes, such as the storage of glucose into glycogen, decrease of glucose output, stimulation of glucose transport into cells, etc. The hormone binds to its receptor, thereby activating an intracellular signaling cascade. Once activated, the insulin receptor (INSR) phosphorylates multiple intracellular substrates, which initiate the downstream signaling pathway. The nature of insulin signaling pathways may vary depending on the organ or tissue. In the central nervous system (CNS), INSRs are expressed in all cell types. This observation may suggest that insulin signaling is involved in important and diverse processes. It regulates glucose metabolism, supports cognitive functions, enhances the outgrowth of neurons, as well as plays a role in the modulation of release and uptake of catecholamine, among other roles. Importantly, insulin can freely cross the blood-brain barrier (BBB) from the circulation and is also synthesized locally within the brain. Insulin resistance (IR) impairs insulin signaling, which may accelerate brain aging, affect plasticity, and potentially contribute to neurodegeneration. Dysregulation of insulin signaling has been implicated in several diseases, including diabetes mellitus, metabolic syndrome, certain cancers, and neurodegenerative diseases, such as Alzheimer's disease. There are two principal insulin signaling pathways: the PI3K/AKT pathway, primarily associated with metabolic effects, and the MAPK pathway, which is involved in cell growth, survival, and gene expression. Our review describes the role of insulin in the human brain, as well as the disturbances in insulin signaling resulting from brain insulin resistance, with a particular focus on its association with Alzheimer's disease.