Role of insulin resistance in Alzheimer's disease

A critical role of insulin resistance (IR) in Alzheimer's disease (AD) includes beta-amyloid (A beta) production and accumulation, the formation of neurofibrillary tangles (NFTs), failure of synaptic transmission and neuronal degeneration. A beta is sequentially cleavaged from APP by two proteolytic enzymes: beta-secretase and gamma-secretase. IR could regulate A beta production via enhancing beta- and gamma-secretase activity. Meanwhile, IR induces oxidative stress and inflammation in the brain which contributes to A beta and tau pathology. A beta accumulation can enhance IR through A beta-mediated inflammation and oxidative stress. IR is a possible linking between amyloid plaques and NFTs pathology via oxidative stress and neuroinflammation. Additionally, IR could disrupt acetylcholine activity, and accelerate axon degeneration and failures in axonal transport, and lead to cognitive impairment in AD. Preclinical and clinical studies have supported that insulin could be useful in the treatment of AD. Thus, an effective measure to inhibit IR may be a novel drug target in AD.