On the one hand, brain insulin resistance reduces the serine phosphorylation of insulin receptor substrate 1, protein kinase B phosphorylation through cascade reactions, and diminished phosphorylation of c-Jun amino-terminal kinase (JNK), which in turn impacts insulin pathway components such as glycogen synthase kinase-3 and protein kinase A. The insulin signaling pathway may be activated by changes in the activity of certain downstream components, which can promote tau protein hyperphosphorylation and neurofibrillary tangle development. Here, INS is linked to Insulin resistance.