Brain insulin resistance and the therapeutic value of insulin and insulin-sensitizing drugs in Alzheimer’s disease neuropathology

The incidence of Alzheimer’s disease (AD) is significantly higher in people with diabetes. Insulin and insulin receptor (IR) signaling intermediates are expressed in the brain. Insulin exerts multiple function in the brain. The role of compromised IR signaling in AD pathogenesis and the therapeutic value of insulin attract broad attention. This review summarizes the collective insulin action in the brain related to key factors of AD pathogenesis, updates the key features of insulin resistance in the AD brain and assesses the therapeutic potential of insulin and insulin-sensitizing drugs. Insulin stimulates neural growth and survival, suppresses amyloidogenic processing of the amyloid precursor protein (AβPP) and inhibits the Tau phosphorylation kinase, glycogen synthase kinase 3β. Central nervous IR signaling regulates systemic metabolism and increases glucose availability to neurons. The expression of IR and its downstream effectors is reduced in AD brain tissues. Insulin and insulin-sensitizing drugs can improve cognitive function in AD patients and AD animal models. Systemic insulin delivery is less effective than intranasal insulin treatment. The penetrance of insulin-sensitizing drugs to the blood brain barrier is problematic and new brain-prone drugs need be developed. Insulin resistance manifested by the degradation and the altered phosphorylation of IR intermediates precedes overt AD syndrome. Type 3 diabetes as a pure form of brain insulin resistance without systemic insulin resistance is proposed as a causal factor in AD. Further research is needed for the identification of critical factors leading to impaired IR signaling and the development of new molecules to stimulate brain IR signaling.