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 α-secretases a disintegrin and metalloprotease 10 (ADAM10) and a disintegrin and metalloprotease 17 (ADAM17), the β-secretase β-site APP cleaving enzyme 1 (BACE1) and γ-secretase and their link to AD. New genetic evidence strengthens the role of α-secretases in AD through cleavage of APP and TREM2. Novel proteins were linked to AD, which control α- and β-secretase activity through transcriptional and post-translational mechanisms. Finally, new opportunities but also challenges are discussed for pharmacologically targeting β- and γ-secretase cleavage of APP and α-secretase cleavage of TREM2 with the aim to prevent or treat AD. • Secreted frizzled-related protein 1, reversion-inducing cysteine-rich protein with Kazal motifs, ataxin-1 and nuclear factor erythroid-derived 2-related factor 2 control a disintegrin and metalloprotease 10 and β-site amyloid precursor protein cleaving enzyme 1 activity and are linked to AD. • New familial Alzheimer Uppsala mutation shifts amyloid precursor protein cleavage from α-to β-secretase. • Structure and pharmacology studies support drug development of γ-secretase modulators. • Triggering receptor expressed on myeloid cells 2 -agonistic antibodies show potential for reducing brain amyloidosis in mice. [ABSTRACT FROM AUTHOR]