Gamma secretase: the final step in the formation of amyloid

Gamma secretase works like a microscopic pair of scissors: in the cells, it cuts long protein chains into shorter sections. One of these sections is amyloid, which clumps together in the brains of Alzheimer's patients and is involved in the development of the disease. Researchers are currently working on so-called gamma secretase modulators that can be used to influence the work of the scissors - in other words, a drug that could prevent the formation of dangerous amyloid.

The scissor function of gamma secretase is part of the complicated process in which amyloid is formed. The starting material is the so-called amyloid precursor protein (APP). This precursor protein is processed in the nerve cells of the brain - a natural process: first it is processed by beta-secretase (also known as BACE1) into a handier section. In a second step, gamma-secretase takes this section and gradually cuts it into smaller pieces. Like a string that is cut into pieces - except that here the string consists of individual amino acids. After every few amino acids, the gamma-secretase cuts this string. The shredded sections produced in this way form the amyloid. Normally, the amyloid is broken down and disposed of as part of the normal metabolism within the cells.

A mutation causes a particularly dangerous type of amyloid to form

However, this is where a special feature comes into play: Usually, amyloid-beta 40 is formed, which comprises 40 amino acids. However, there are other types of amyloid - including amyloid beta 42, which clumps together easily and thereby forms dangerous amyloid plaques. Certain mutations in the gamma-secretase produce a particularly large amount of this amyloid-beta 42.

In this context, researchers use the term “impaired processivity” of gamma secretase: the scissors no longer cut as well due to the mutations - in other words, they do not properly process the string that they are supposed to cut into small pieces. This results in the increased production of these longer, dangerous peptides. Recent studies have shown that the deterioration in processivity correlates with the onset of the disease in mutation carriers. In plain language: the worse a person's gamma secretase works, the earlier they will develop Alzheimer's disease.

The role of presenilin proteins

Gamma secretase is a protein complex consisting of different components. The presenilin protein, which forms the blades of the scissors, plays a central role. If the corresponding gene mutates, this accelerates the formation of amyloid deposits and thus the development of Alzheimer's disease. Presenilin mutations are a frequent trigger of the early-onset, hereditary form of Alzheimer's disease. They are therefore an important starting point for research work.

Active substances to influence gamma secretase are currently undergoing clinical trials

After researchers discovered gamma secretase more than two decades ago and gradually deciphered how it works, there were initially attempts to use so-called inhibitors to stop the process altogether so that no more amyloid is produced. However, these attempts failed because gamma secretase also fulfills other important cellular tasks. These functions would also be blocked by the inhibitors, resulting in significant side effects.

Medical research is therefore currently looking for gamma secretase modulators. These are active substances with which the processivity can be increased so that the scissors again cut better and produce shorter peptides. Scientists hope that this will slow down the progression of the disease and even makes prevention possible. Ideally, the gamma secretase modulators should be administered early in the course of the disease, because the amyloid plaques form many years before the first symptoms of the disease appear. Such a drug is currently undergoing clinical trials.

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