Secretases in Alzheimer's disease: Novel insights into proteolysis of APP and TREM2

Secretases are a group of proteases that are major drug targets considered for the prevention and treatment of Alzheimer's disease (AD). Secretases do not only process the AD-linked neuronal amyloid precursor protein (APP) but also the triggering receptor expressed on myeloid cells 2 (TREM2), thereby controlling microglial functions. This review highlights selected recent discoveries for the a-secretases a disintegrin and metalloprotease 10 (ADAM10) and a disintegrin and metalloprotease 17 (ADAM17), the beta-secretase beta-site APP cleaving enzyme 1 (BACE1) and gamma-secretase and their link to AD. New genetic evidence strengthens the role of alpha-secretases in AD through cleavage of APP and TREM2. Novel proteins were linked to AD, which control alpha- and beta-secretase activity through transcriptional and post-translational mechanisms. Finally, new opportunities but also challenges are discussed for pharmacologically targeting beta- and gamma-secretase cleavage of APP and alpha-secretase cleavage of TREM2 with the aim to prevent or treat AD.