ADAM10: A protective shield against the harmful amyloid

The ADAM10 enzyme can be imagined as a pair of scissors: In the nerve cells of the brain, it attaches itself to a specific protein, which it then cuts - this "enzymatic cleavage", as the cut is called in scientific terminology, is an important part of the protective mechanism against Alzheimer's disease. If ADAM10 no longer works reliably due to a mutation, the risk of developing the disease increases considerably.

ADAM10 belongs to the alpha-secretase family and is indirectly related to amyloid - the substance that is accumulated in the brain of Alzheimer's patients and plays a key role in the development of the disease. This amyloid is formed in nerve cells from a precursor protein called APP (amyloid precursor protein). If this APP is cut, amyloid can be formed - but not necessarily: some of the APP proteins are further processed by BACE1; in this case, amyloid is formed at the end of a complex process. However, another part of the APP proteins is not cut by BACE1, but by ADAM10. And no dangerous amyloid develops from them.

All of these processes occur naturally in every human being. It is crucial that the balance is maintained: Normally, the body can cope with the produced amyloid. A problem only arises if too much amyloid is formed. In some cases, this happens when BACE1 is hyperactive. However, it can also happen that ADAM10 does not work sufficiently: It then processes too few of the APP, which subsequently also transform into amyloid. The balance is thus disturbed.

There are gene mutations that lead to ADAM10 becoming less active or even failing completely. However, ADAM10 is not only a protective factor against the formation of amyloid, but is also of crucial importance for brain development in general. Research has shown, for example, that mice do not survive in the embryonic phase if they lack ADAM10; their brains then do not develop sufficiently.

For Alzheimer's disease, researchers are working on drugs that can be used to artificially stimulate ADAM10. Their use is conceivable in two cases: Firstly, when ADAM10 is not working well enough. And secondly, when BACE1 is hyperactive and forms too much amyloid. In this case, increased ADAM10 activity could restore the disturbed balance. There is even speculation that high ADAM10 activity could compensate for cognitive deficits that already exist. It is therefore possible that it not only plays a role in prevention, but can even contribute to healing. This has already been achieved in a mouse model. However, all of these possible effects are a long way off: there are currently no corresponding drugs in clinical trials.

The abbreviation ADAM refers to "a disintegrin and metalloproteinase". Metalloproteases are enzymes that require a metal ion as a catalyst for their task - the cutting of proteins. In the case of ADAM10, this is zinc. However, there is not just this one metalloprotease: a whole family of ADAM proteins is known in research, consisting of almost two dozen members, each carrying a number. They all fulfil different functions; ADAM10 is considered the most relevant of these substances with regard to Alzheimer's disease.

^{_{Status as of 13.08.2024}}