Inside our cells, an enzyme called γ-secretase (gamma-secretase) acts like a pair of biological scissors embedded within the cell’s membrane. Its primary job is to cut other proteins located in the same membrane, a process called cleavage. This action is a necessary event in cellular biology that initiates a variety of processes.
The Molecular Machinery of γ-Secretase
The γ-secretase enzyme is a sophisticated assembly of four distinct protein components: presenilin (PS), nicastrin (NCT), anterior pharynx-defective 1 (APH-1), and presenilin-enhancer 2 (PEN-2). The assembly begins with APH-1 and nicastrin forming a scaffold, which is then joined by presenilin and PEN-2 to complete the complex.
Presenilin contains the active site that performs the protein-cutting action, a process known as intramembrane proteolysis. This specialized cleavage occurs within the oily, lipid bilayer of the cell membrane. This is an unusual environment for such a reaction, as most protein cleavage happens in the watery fluid inside or outside the cell. The γ-secretase complex creates a protected, water-containing chamber within the membrane to facilitate this precise cutting of its target proteins.
The four protein subunits have distinct roles. Nicastrin functions as a receptor to recognize and bind target proteins, known as substrates. APH-1 provides structural stability to the complex. PEN-2 is involved in the final activation step, which involves a self-cleavage of the presenilin subunit to create the mature, functional enzyme.
The Link to Alzheimer’s Disease
The function of γ-secretase is associated with Alzheimer’s disease through its interaction with the amyloid precursor protein (APP). APP is a large protein spanning the cell membrane that is processed by enzymatic cuts. In one pathway, β-secretase first cleaves APP, leaving a fragment known as C99 in the membrane, which γ-secretase then acts upon.
This final cut by γ-secretase releases a peptide called amyloid-beta (Aβ). The enzyme is not perfectly precise and can cut at slightly different points along the C99 fragment. This results in Aβ peptides of different lengths, most commonly Aβ40 and Aβ42.
The longer Aβ42 version is more problematic because it is “stickier” and prone to aggregation. These peptides clump together, forming small toxic clusters (oligomers) and eventually the large, insoluble amyloid plaques that are a hallmark of Alzheimer’s disease. An increased ratio of Aβ42 to Aβ40 is a common biochemical feature observed in inherited, early-onset forms of the disease. The accumulation of these plaques and oligomers is believed to trigger inflammation and neuronal damage, leading to cognitive decline.
Essential Biological Roles
While its role in producing amyloid-beta is linked to disease, γ-secretase performs functions necessary for cellular health and development. The enzyme cleaves over 140 different substrate proteins, highlighting its involvement in a wide range of biological activities. One of its primary functions is the processing of the Notch receptor, a protein for cell-to-cell communication.
Notch signaling is a highly conserved pathway that allows adjacent cells to coordinate their fates, regulating processes like cell proliferation, differentiation, and survival. Similar to its action on APP, γ-secretase cleaves the Notch protein after an initial cut has been made by another enzyme. This cleavage releases the Notch intracellular domain (NICD) into the cell’s cytoplasm.
Once freed, the NICD travels to the cell nucleus, where it acts as a transcriptional regulator, binding to DNA and switching specific genes on or off. This activation of target genes controls developmental decisions, such as whether a stem cell differentiates into a neuron or another type of cell. This process is active throughout life and is involved in tissue maintenance and repair in adults.
Targeting γ-Secretase for Treatment
Given that γ-secretase produces the Aβ peptides that form amyloid plaques, it became an early target for Alzheimer’s therapies. The initial strategy was to develop drugs that block the enzyme’s activity entirely. These compounds, known as γ-secretase inhibitors (GSIs), were designed to shut down the production of all Aβ peptides to prevent plaque formation.
However, this approach encountered significant problems in clinical trials. Because GSIs are not selective, they inhibit all functions of γ-secretase, including the necessary cleavage of the Notch receptor. Disrupting Notch signaling leads to severe side effects by interfering with the normal function of cells in tissues like the intestines and the immune system. These toxic effects made broad-spectrum GSIs an unviable treatment strategy for a chronic condition like Alzheimer’s.
This challenge led to the development of a more sophisticated class of drugs called γ-secretase modulators (GSMs). Instead of blocking the enzyme, GSMs subtly alter its cutting action on APP. These molecules cause γ-secretase to shift its cleavage preference, resulting in the production of fewer aggregation-prone Aβ42 peptides and more of the shorter, less harmful Aβ species like Aβ38. The appeal of GSMs lies in their selectivity; they modulate APP processing without significantly affecting the cleavage of Notch or other substrates, thus avoiding the toxicity that plagued early inhibitors.