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

Stefan F Lichtenthaler, Sarah K Tschirner, Harald Steiner

Current opinion in neurobiology 2022 Feb

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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.

Citation

Stefan F Lichtenthaler, Sarah K Tschirner, Harald Steiner. Secretases in Alzheimer's disease: Novel insights into proteolysis of APP and TREM2. Current opinion in neurobiology. 2022 Feb;72:101-110