The Distinct Role of ADAM17 in APP Proteolysis and Microglial Activation Related to Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease with the symptom of cognitive impairment. The deposition of amyloid beta (A beta) peptide is believed to be the primary cause to neuronal dystrophy and eventually dementia. A beta is the proteolytic product from its precursor amyloid precursor protein (APP) by beta- and gamma- secretase. An optional cleavage by alpha-secretase happens inside the A beta domain. ADAM17 is supposed to be the regulated alpha-secretase of APP. Enhanced activity of ADAM17 leads to the increasing secretion of neuroprotective soluble APP alpha fragment and reduction of A beta generation, which may be benefit to the disease. ADAM17 is then considered the potential therapeutic target for AD. Microglia activation and neuroinflammation is another important event in AD pathogenesis. Interestingly, ADAM17 also participates in the cleavage of many other membrane-bound proteins, especially some inflammatory factors related to microglia activation. The facilitating role of ADAM17 in inflammation and further neuronal damage has also been illustrated. In results, the activation of ADAM17 as the solution to AD may be a tricky task. The comprehensive consideration and evaluation has to be carried out carefully before the final treatment. In the present review, the distinct role of ADAM17 in AD-related APP shedding and neuroinflammatory microglial activation will be carefully discussed.