Insulin enters the brain through one of three routes: blood-brain barrier, median eminence, or the vascular endothelium by transport proteins. Insulin levels vary throughout the brain, the olfactory bulb is thought to have the highest level, this is mainly due to the high concentration of IRs. When insulin and IR bind this, two branches of insulin signaling are activated, MAPK and PI3-Akt Pathways. IGF1R also activates PI3K. IR and IGF1R both belong to the RTK family. When insulin binds this causes the IR to change this change initiates autophosphorylation and attracts IRS proteins, while the IRS is being activated there are phosphorylation sites inactivating the IRS by making them separate from the insulin receptor and reducing the addition of phosphate groups to tyrosine. Tyrosine-phosphorylated IRS activates PI3Ks, PI3K is a heterometric protein, and its SH2 domain; P85 binds to phosphoserines, P110 changes phosphatidylinositol (3,4)-bisphosphate (PIP2) into phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which results in the activation of many downstream kinases. Akt is from the family of serine/threonine kinases and consists of three isoforms, Akt1, Akt2, and Akt3. These forms showed varied expression in the brain and cells based on their location, an example is how Akt1 and Akt3 are distributed through somatic layers of the hippocampus, however, Akt2 is expressed in astrocytes instead and not neurons. Upon activation, Akt is activated with the PH domain of PIP3 and this then allows PIP3 to phosphorylate threonine. There was a study conducted that measured insulin in low levels of the brain; in humans and rodents, the research revealed that reductions in brain insulin were consistent in both Alzheimer’s patients and age-matched individuals without Alzheimer’s, suggesting that the decline in brain insulin is more likely associated with aging rather than specifically with Alzheimer’s disease. One study couldn’t find insulin mRNA in the cortex, while another study did, making it challenging to interpret the mRNA data. To fully understand insulin’s role in healthy and diseased brains, more research needs to be done to explore its relationship with the severity of Alzheimer’s disease and age-matched controls. However Ongoing studies consistently show that administering insulin, either through intravenous infusion or intranasal delivery, can slightly improve performance on memory tasks for both healthy adults and individuals with Alzheimer’s disease or mild cognitive impairment (MCI) at dosage levels.
