Gamma secretase is a multi-subunit protease complex that acts like molecular scissors within the cell membrane. This enzyme is made up of four core components: presenilin, nicastrin, APH-1, and PEN-2. Inhibitors are compounds designed to block the activity of an enzyme. Gamma secretase inhibitors are substances that block its cutting functions.
The Enzyme’s Natural Functions
Gamma secretase plays a widespread role in the body by cleaving over 90 different integral membrane proteins. This enzyme complex is an intramembrane protease, cutting within the membrane-spanning domain of its target proteins. The presenilin subunit is the catalytic component, containing the active site where the cutting action occurs.
One well-understood function involves the Notch signaling pathway, which is fundamental for cell-to-cell communication during development. When a Notch receptor binds to its ligand on a neighboring cell, it undergoes a series of cleavages, with gamma secretase performing the final cut to release the Notch intracellular domain (NICD). This NICD then moves into the cell’s nucleus, where it regulates gene transcription, influencing cell proliferation, differentiation, and cell fate.
The enzyme also processes the amyloid precursor protein (APP), a large membrane protein. APP is sequentially cleaved by beta-secretase and then gamma secretase, producing various amyloid-beta (Aβ) peptides. Under normal conditions, these peptides are cleared from the brain.
How Gamma Secretase Inhibitors Work
Gamma secretase inhibitors (GSIs) are compounds that interfere with the cutting action of the gamma secretase enzyme. These inhibitors can bind to different parts of the four-subunit gamma secretase complex, preventing it from properly interacting with and cleaving its target proteins. By blocking the enzyme’s active site, GSIs prevent the release of intracellular fragments that would normally trigger downstream cellular processes.
One way to think about this is like a lock and key mechanism, where the enzyme is the lock and its natural protein targets are the keys. A gamma secretase inhibitor acts as a faulty key that gets stuck in the lock, preventing the correct key from turning and opening it.
Applications in Disease Research
Gamma secretase inhibitors have been extensively studied as potential treatments for several diseases, particularly Alzheimer’s disease. The “amyloid hypothesis” suggests that the accumulation of amyloid-beta (Aβ) peptides, especially Aβ42, is a primary driver of Alzheimer’s disease pathology. Since gamma secretase is directly involved in producing Aβ from APP, inhibiting this enzyme was a logical strategy to reduce Aβ levels and prevent plaque formation in the brain.
Beyond Alzheimer’s disease, gamma secretase inhibitors have also been investigated in certain types of cancer. The Notch signaling pathway, a known target of gamma secretase, is overactive in various cancers, including breast and ovarian cancers. By inhibiting gamma secretase, researchers aimed to block the release of the Notch intracellular domain (NICD), thereby suppressing the uncontrolled cell proliferation and survival that characterizes these malignancies.
Current Research and Considerations
Early clinical trials for Alzheimer’s disease with gamma secretase inhibitors, such as semagacestat and avagacestat, faced significant challenges. These trials resulted in unfavorable risk-benefit profiles, showing no significant beneficial effects on cognitive decline and even a worsening of cognitive indicators. A major concern was the occurrence of side effects, including gastrointestinal issues like diarrhea, skin problems such as rashes and skin cancers, and immune system effects affecting B- and T-lymphocytes.
These adverse effects are largely attributed to the non-selective inhibition of gamma secretase, which interferes with its other normal functions, particularly the Notch signaling pathway. Because Notch signaling is involved in many cellular processes, including cell differentiation and tissue maintenance, broad inhibition can lead to unwanted systemic toxicity. This led to a shift in research focus towards developing more selective inhibitors or modulators.
Current research efforts aim to develop next-generation gamma secretase modulators (GSMs) that can selectively reduce the production of the more harmful Aβ42 peptide while sparing Notch and other gamma secretase substrates. These modulators do not block the enzyme completely but rather alter its activity to produce less aggregation-prone Aβ forms. Some of these compounds are being explored for their potential in combination therapies with other drugs that target different aspects of disease pathology, hoping to achieve better efficacy and safety profiles.