Probing Mechanisms and Therapeutic Potential of γ-Secretase in Alzheimer’s Disease
The membrane-embedded γ-secretase complex carries out hydrolysis within the lipid bilayer in proteolyzing nearly 150 different membrane protein substrates. Among these substrates, the amyloid precursor protein (APP) has been the most studied, as generation of aggregation-prone amyloid β-protein (Aβ)...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/2/388 |
| _version_ | 1827601392702849024 |
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| author | Michael S. Wolfe |
| author_facet | Michael S. Wolfe |
| author_sort | Michael S. Wolfe |
| collection | DOAJ |
| description | The membrane-embedded γ-secretase complex carries out hydrolysis within the lipid bilayer in proteolyzing nearly 150 different membrane protein substrates. Among these substrates, the amyloid precursor protein (APP) has been the most studied, as generation of aggregation-prone amyloid β-protein (Aβ) is a defining feature of Alzheimer’s disease (AD). Mutations in APP and in presenilin, the catalytic component of γ-secretase, cause familial AD, strong evidence for a pathogenic role of Aβ. Substrate-based chemical probes—synthetic peptides and peptidomimetics—have been critical to unraveling the complexity of γ-secretase, and small drug-like inhibitors and modulators of γ-secretase activity have been essential for exploring the potential of the protease as a therapeutic target for Alzheimer’s disease. Such chemical probes and therapeutic prototypes will be reviewed here, with concluding commentary on the future directions in the study of this biologically important protease complex and the translation of basic findings into therapeutics. |
| first_indexed | 2024-03-09T04:55:47Z |
| format | Article |
| id | doaj.art-16f8a81d40d347e2bd7b89188b613f58 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T04:55:47Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-16f8a81d40d347e2bd7b89188b613f582023-12-03T13:05:09ZengMDPI AGMolecules1420-30492021-01-0126238810.3390/molecules26020388Probing Mechanisms and Therapeutic Potential of γ-Secretase in Alzheimer’s DiseaseMichael S. Wolfe0Department of Medicinal Chemistry, University of Kansas, 1567 Irving Hill Road, GLH-2115, Lawrence, KS 66045, USAThe membrane-embedded γ-secretase complex carries out hydrolysis within the lipid bilayer in proteolyzing nearly 150 different membrane protein substrates. Among these substrates, the amyloid precursor protein (APP) has been the most studied, as generation of aggregation-prone amyloid β-protein (Aβ) is a defining feature of Alzheimer’s disease (AD). Mutations in APP and in presenilin, the catalytic component of γ-secretase, cause familial AD, strong evidence for a pathogenic role of Aβ. Substrate-based chemical probes—synthetic peptides and peptidomimetics—have been critical to unraveling the complexity of γ-secretase, and small drug-like inhibitors and modulators of γ-secretase activity have been essential for exploring the potential of the protease as a therapeutic target for Alzheimer’s disease. Such chemical probes and therapeutic prototypes will be reviewed here, with concluding commentary on the future directions in the study of this biologically important protease complex and the translation of basic findings into therapeutics.https://www.mdpi.com/1420-3049/26/2/388proteaseamyloidAlzheimer’s diseaseinhibitorsmodulators |
| spellingShingle | Michael S. Wolfe Probing Mechanisms and Therapeutic Potential of γ-Secretase in Alzheimer’s Disease Molecules protease amyloid Alzheimer’s disease inhibitors modulators |
| title | Probing Mechanisms and Therapeutic Potential of γ-Secretase in Alzheimer’s Disease |
| title_full | Probing Mechanisms and Therapeutic Potential of γ-Secretase in Alzheimer’s Disease |
| title_fullStr | Probing Mechanisms and Therapeutic Potential of γ-Secretase in Alzheimer’s Disease |
| title_full_unstemmed | Probing Mechanisms and Therapeutic Potential of γ-Secretase in Alzheimer’s Disease |
| title_short | Probing Mechanisms and Therapeutic Potential of γ-Secretase in Alzheimer’s Disease |
| title_sort | probing mechanisms and therapeutic potential of γ secretase in alzheimer s disease |
| topic | protease amyloid Alzheimer’s disease inhibitors modulators |
| url | https://www.mdpi.com/1420-3049/26/2/388 |
| work_keys_str_mv | AT michaelswolfe probingmechanismsandtherapeuticpotentialofgsecretaseinalzheimersdisease |