APP: At the source of Alzheimer's disease

In research, Alzheimer's is often described as a cascade - a sequence of many different processes leading to the typical symptoms of the disease. If you trace this cascade back to its beginning, you end up with APP: the amyloid precursor protein (APP for short). Many years or even decades before patients notice the first symptoms, a process begins with the normally harmless protein APP, at the end of which there is far-reaching destruction of the brain.

The APP protein is found in many tissues of the human body; it is particularly present in the nerve cells of the brain, where APP spans the membrane of the cell so that part of the protein protrudes into the cell and another part protrudes out of it. However, scientists have not yet conclusively discovered exactly what role it plays in the highly complex neurobiological processes that take place naturally in the body.

The path from APP to amyloid

Like all proteins, APP is processed by the organism. Cells, proteins and all other living components of the body are never static; various processes are constantly taking place that are a prerequisite for life. And one of these processes is the conversion of the amyloid precursor protein.

The APP can be imagined as a chain consisting of individual amino acids. There are exactly 753 of them. During processing, this chain is cut into smaller pieces, and this happens in two main ways.

Number one is the so-called “non-amyloidogenic pathway”. Here, an enzyme called ADAM10 (it acts like a pair of molecular scissors) processes the APP. The small pieces coming out are harmless.

Number two is the “amyloidogenic pathway”. Here, two enzymes process the APP one after the other: first the beta-secretase and then the gamma secretase. This pathway produces beta-amyloid (amyloid for short), which can clump together. These aggregations - known as plaques - are considered to trigger the further disease cascade in Alzheimer's.

Genetic risk

The amyloid precursor protein is found in all people. However, there are mutations that influence the likelihood of developing Alzheimer's disease. For example, a rare mutation in the APP gene called A673T (also known as the “Icelandic mutation”) reduces the formation of amyloid by up to 40 percent and is therefore seen as a protective factor against Alzheimer's disease. Other mutations, however, have the opposite effect by stimulating the production of amyloid.

The APP gene is located on chromosome 21 - the chromosome that is present three times in trisomy 21 patients (Down syndrome) instead of the usual two. As a result, a particularly large number of amyloid precursor proteins are formed in them, which leads to excessive amyloid production. This is why almost all people with this genetic defect also develop Alzheimer's - the first typical changes in the brain usually occur in them around the age of 40, i.e. significantly earlier than in almost all other Alzheimer's patients.

Hope for a new therapy

Active substances targeting the amyloid precursor protein are currently being developed. There are two approaches: The first one focuses on inhibiting the synthesis of the protein. The second approach attempts to inhibit the enzymes that cut out the components which form Alzheimer's plaques from the amyloid precursor protein.

Drugs that intervene in the neurobiological processes in Alzheimer's patients at a later stage are more advanced - and have recently been approved in some countries. Through passive immunization, they cause the amyloid plaques to be broken down. This slows down the entire disease cascade - and although the disease is not stopped, it is decelerated. Studies have shown that drugs targeting amyloid must be used early in the course of the disease.

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