ADAM10: α-Secretase in Alzheimer Disease and regulator in neurobiology

The proteolytic and amyloidogenic processing by beta-secretase and gamma-secretase of the amyloid precursor protein (APP) is a pathological hallmark of Alzheimer's Disease (AD). These proteolytic activities lead to the release of amyloid beta-peptides discussed to cause the neurological pathology and to be linked with the pathological progress in AD. Due to its capability to cleave APP within the toxic peptide sequence the role of the metalloproteinase ADAM10 is known as an antagonist of the disease-causing pathway. ADAM10 also plays a major role in ectodomain shedding of a number of important cell surface proteins. In addition ADAM10 is involved in the proteolytic activation cascade of the Notch receptor which is of crucial function in developmental processes. The study of ADAM10-deficient mice also revealed that ADAM10 regulates synaptic function and synaptogenesis. A pharmacological activation of ADAM10 is discussed to represent a valuable strategy for the prevention of AD. Due to the multiple roles of ADAM10 in the brain it will be challenging to find a suitable therapeutic window.