1. Secretases in Alzheimer's disease: Novel insights into proteolysis of APP and TREM2
- Author
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Harald Steiner, Sarah K. Tschirner, and Stefan F. Lichtenthaler
- Subjects
Proteases ,therapeutic use [Membrane Glycoproteins] ,ADAM10 ,Proteolysis ,genetics [Amyloid Precursor Protein Secretases] ,metabolism [Amyloid beta-Peptides] ,therapeutic use [Amyloid beta-Peptides] ,therapeutic use [ADAM10 Protein] ,ADAM10 Protein ,Amyloid beta-Protein Precursor ,Alzheimer Disease ,mental disorders ,metabolism [Amyloid beta-Protein Precursor] ,Amyloid precursor protein ,Disintegrin ,medicine ,Aspartic Acid Endopeptidases ,Humans ,therapeutic use [Receptors, Immunologic] ,ddc:610 ,Receptors, Immunologic ,therapeutic use [Amyloid beta-Protein Precursor] ,Metalloproteinase ,Amyloid beta-Peptides ,Membrane Glycoproteins ,biology ,medicine.diagnostic_test ,TREM2 ,General Neuroscience ,therapeutic use [Amyloid Precursor Protein Secretases] ,metabolism [Receptors, Immunologic] ,metabolism [Aspartic Acid Endopeptidases] ,metabolism [Amyloid Precursor Protein Secretases] ,genetics [Amyloid beta-Protein Precursor] ,genetics [Aspartic Acid Endopeptidases] ,therapeutic use [Aspartic Acid Endopeptidases] ,biology.protein ,metabolism [ADAM10 Protein] ,Amyloid Precursor Protein Secretases ,Neuroscience ,Amyloid precursor protein secretase ,metabolism [Membrane Glycoproteins] - 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.
- Published
- 2022