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

Curr Opin Neurobiol. 2022 Feb:72:101-110. doi: 10.1016/j.conb.2021.09.003. Epub 2021 Oct 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • ADAM10 Protein / metabolism
  • ADAM10 Protein / therapeutic use
  • Alzheimer Disease*
  • Amyloid Precursor Protein Secretases* / genetics
  • Amyloid Precursor Protein Secretases* / metabolism
  • Amyloid Precursor Protein Secretases* / therapeutic use
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / therapeutic use
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Amyloid beta-Protein Precursor / therapeutic use
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism
  • Aspartic Acid Endopeptidases / therapeutic use
  • Humans
  • Membrane Glycoproteins / metabolism
  • Membrane Glycoproteins / therapeutic use
  • Proteolysis
  • Receptors, Immunologic / metabolism
  • Receptors, Immunologic / therapeutic use


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • TREM2 protein, human
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • ADAM10 Protein