BACE1: A crucial enzyme in the formation of amyloid

When the enzyme BACE1 was discovered at the turn of the millennium, hope for an effective Alzheimer's drug flared up for a moment: The enzyme is involved in the formation of amyloid plaques in the brain - the deposits that are found in Alzheimer's patients. The hypothesis at the time was that if the activity of BACE1 could be suppressed, the formation of amyloid beta, which accumulates in the plaques, could be reduced. This approach was considered to delay or even prevent the onset of Alzheimer's disease.

In the meantime, several so-called inhibitors have been tested; these are drugs that are intended to restrict the activity of BACE1. However, the active substances did not bring about any improvement and the trials have failed. Nevertheless, BACE1 is still regarded as the key to amyloid plaques; research therefore continues to focus intensively on the enzyme and its function.

BACE1 is another term for beta-secretase, an enzyme from the protease family. The proteases cleave other proteins and thus change them. BACE1 occurs naturally in every human being and plays a role in a wide variety of cell types throughout the body. The BACE1 enzymes that are found in brain cells are involved in the formation of beta-amyloid.

Beta-amyloid is formed through a complex process in several steps from a precursor protein called APP (amyloid precursor protein). The APP undergoes what is known as enzymatic cleavage - and this is precisely where BACE1 comes into play. The first and therefore decisive step in the cascade is cleavage by BACE1. One of the products resulting from this cleavage is converted into amyloid beta by gamma secretase in the next step.

The risk of developing Alzheimer's disease has a genetic component. Several, albeit rare, variants of the amyloid precursor protein APP are known to greatly increase or decrease the risk of the disease. And this is precisely one of the risk factors for Alzheimer's disease: some of these APP variants are processed better by BACE1, others worse. Depending on this, more or less of the high-risk amyloid is produced in each person. People with trisomy 21, for example, have a greatly increased risk of Alzheimer's because they have three copies of chromosome 21, which also contains the gene for APP. As a result, more beta-amyloid is formed.

BACE1 is seen as a potential target for an Alzheimer's drug. The inhibitors are intended to slow down the activity of BACE1. Why the previous studies have failed has not yet been finally explained. One of the reasons could be that the therapy was started too late - at a time when the test subjects were already complaining of cognitive impairment. It is possible that the disease had already progressed too far. One option for research is therefore to try out such a BACE1 therapy at an earlier stage in the course of the disease. However, because BACE1 has more functions than just processing the amyloid precursor protein, suppressing this enzyme could lead to it also failing to fulfil desirable - and necessary - tasks within the cell. In previous studies, BACE1 was very strongly suppressed by 80 per cent, which may have led to unintended side effects. It is possible that better results can be achieved with a less strong inhibition.

Another possible application for such an inhibitor is in the later course of the disease: There are now antibodies that can be used to remove the amyloid plaques in the brain; these drugs are authorised in many countries such as the USA, but not in the EU. It is possible that a BACE1 inhibitor could be administered after such a therapy to prevent new plaques from forming.

^{_{Status as of 13.08.2024}}