Selective Inhibition of Gamma-Secretase Activity on APP and Notch
Author Information
Author(s): Yang Ting, Arslanova Dilyara, Gu Yongli, Augelli-Szafran Corinne, Xia Weiming
Primary Institution: Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Harvard University, Boston, MA, USA
Hypothesis
Can gamma-secretase inhibitors selectively block the cleavage of amyloid precursor protein (APP) without affecting Notch signaling?
Conclusion
The study demonstrates that compound E selectively inhibits Aβ production while having minimal effects on Notch cleavage.
Supporting Evidence
- Compound E completely blocked Aβ generation from APP cleavage.
- DAPT and compound E were more effective in blocking Aβ generation than NICD generation.
- Zebrafish treated with DAPT showed significant morphological defects consistent with Notch signaling inhibition.
- Compound E had a much higher EC50 for inhibiting Notch-Aβ-like peptide production compared to Aβ.
Takeaway
This study found a way to block a harmful protein linked to Alzheimer's disease without affecting a protein important for development.
Methodology
The study used a combination of in vitro assays, cell-based assays, and zebrafish models to evaluate the effects of gamma-secretase inhibitors.
Limitations
The study primarily focuses on two inhibitors and may not represent the full spectrum of gamma-secretase modulation.
Digital Object Identifier (DOI)
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