Secretases in Alzheimer's disease: Novel insights into proteolysis of APP and TREM2
Open accessAbstract
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.
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The observed association between age at dementia onset and variants in TSPAN14 and TSPAN10, both with a deleterious correlation, may result from disruption of a protective role of ADAM10.
“the basis of the observed association between age of dementia onset and these variants in TSPAN14 and TSPAN10 (both with a deleterious correlation) may result from disruption of a protective role of ADAM10.”
From Genetic associations with age at dementia onset in the <i>PSEN1 E280A</i> Colombian kindred (2023) · cites this paper as [49]
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References 75 · Cited by 60
Research works printed but not linked: 2
- Selection of candidate highlight papers 2019, 2020, 2021 Papers of special interest (*): Bahn PNAS 2019: A signaling pathway involving the transcription factor Nrf2 is shown to suppress BACE1 transcription and ameliorate cognitive deficits in an Alzheimer's disease mouse model. Brummer EMBO Mol Med 2019: Using proteomics and CSF samples from a phase 2a clinical trial, this study reports that activation of the a-secretase ADAM10 may be feasible in a substrate-specific manner. Das Mol Psychiatry 2021: This study reports that positive allosteric modulators of metabotropic glutamate receptor 1 may alleviate cognitive worsening induced by clinically tested BACE1 inhibitors. Deming Sci Transl Med 2019: Using genetics and functional analysis, this study identified the MS4A gene cluster as a modifier of TREM2 shedding in Alzheimer's disease.
- Nakamura Sci Transl Med 2019: Using mice, this study unravels a neuronal signaling pathway that controls ADAM10 activity and Ab generation in mice. Pagnon de la Vega, Sci Transl Med 2021 in press: This study identifies the first deletion within the Ab sequence of APP that causes dominantly inherited Alzheimer's disease. region denotes the ADAM protease cleavage site at amino acid 157. A point mutation at this site, H157Y, which causes AD, enhances ADAM protease cleavage of TREM2, presumably reducing the protective TREM2 functions. B. Therapeutic targeting of TREM2 shedding. Agonistic antibodies such as 4D9 that prevent ectodomain shedding likely cause receptor cross-linking and trigger defense mechanisms to AD pathology from FL TREM2-mediated signaling.
- Authors
- Lichtenthaler, S. F., Tschirner, S. K., & Steiner, H.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- Corresponding author
- Lichtenthaler, Stefan F.
- Steiner, Harald
- Venue
- Current Opinion in Neurobiology
- Publisher
- Elsevier BV
- Published
- 2022-02
- Volume
- 72
- Pages
- 101-110
- ISSN
- 0959-4388 (ISSN-L)
- OpenAlex
- W3210575413
- Cited by
- 60
- References
- 75
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 17 · 2023: 10 · 2022: 13
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Opinion in Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- DZNE Pub (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (263531414/FOR2290)
- Bundesministerium für Bildung und Forschung
- EU Joint Programme – Neurodegenerative Disease Research (01ED2002B, FKZ161L0214C)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, secretases, amyloid precursor protein, TREM2, ADAM10, ADAM17, BACE1, gamma-secretase, alpha-secretase, microglial function, APP cleavage, secretase inhibitors, genetic evidence
- MeSH terms
- ADAM10 Protein, Alzheimer Disease, Humans, Membrane Glycoproteins, Receptors, Immunologic, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Amyloid Precursor Protein Secretases, Proteolysis
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