Secretases in Alzheimer's disease: Novel insights into proteolysis of APP and TREM2
- PMID: 34689040
- DOI: 10.1016/j.conb.2021.09.003
Secretases in Alzheimer's disease: Novel insights into proteolysis of APP and TREM2
Abstract
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.
Copyright © 2021 Elsevier Ltd. All rights reserved.
Conflict of interest statement
Conflict of interest statement H.S. and S.K.T. declare no conflict of interest. S.F.L. has research collaborations on BACE inhibitors with Novartis and Shionogi.
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