Another mutation found against Alzheimer’s disease

Alzheimer’s disease in most cases manifests itself in very old people, somewhere in their seventy or eighty years. This is a sporadic form of the disease that occurs without a rigid genetic condition. That is, a person may have mutations that increase its likelihood (for example, the famous gene variants APOE, which we have repeatedly written about), but this is exactly what the increase in probability is – the disease may not happen. Molecular abnormalities in the brain (the notorious deposits of toxic proteins) begin to appear long before clinical symptoms, and the disease progresses relatively slowly.

But there is another form of Alzheimer’s disease, hereditary. Here we are talking about mutations with which it will no longer be possible to avoid it, or the probability of this is extremely low. Such mutations are found when family histories of Alzheimer’s disease are studied when it occurs in the same family from generation to generation. Mutations in hereditary “Alzheimer’s” are often found in the gene DOG1, which encodes the protein presenilin-1. It is part of a large enzyme complex, which, in turn, determines the amount of beta-amyloid, one of the toxic Alzheimer’s proteins. When there is too much beta-amyloid in the brain, it literally precipitates, poisoning the life of neurons. The hereditary form of Alzheimer’s disease is much rarer than the sporadic one, but on the other hand, it does not manifest itself in old age, but right after forty years, and these are not invisible molecular pathologies, but already clinical symptoms.

We said above that the probability of avoiding hereditary “Alzheimer’s” is extremely low, but it is not equal to zero. It happens that a person has other mutations that compensate for the effect of Alzheimer’s mutations. A few years ago employees Harvard UniversityUniversity of Antioquia and other research centers told in Nature about a Colombian woman who lived to the age of seventy without any signs of Alzheimer’s disease, although she had a mutation in the gene DOG1, and the disease should have manifested in her more than thirty years ago. She was saved by another mutation, in the gene APOE – he was in her usual form APOE3which most people have, but in its APOE3 there were features that interrupted the negative impact of Alzheimer’s DOG1.

IN new article the same researchers talk about a man from the same family who also had an Alzheimer’s mutation in DOG1 and who lived to age 67 with no Alzheimer’s problems with memory or anything. He had an anti-Alzheimer’s mutation elsewhere – in the gene RELN. After death, both brains, both female and male, were given to researchers by the decision of their relatives, and here some oddities were discovered. When they talk about Alzheimer’s disease, they immediately remember toxic protein accumulations – we also remembered them a little higher. Accumulations are different: there are accumulations of beta-amyloid, which form the so-called amyloid plaques, and accumulations of tau protein, which form neurofibrillary tangles. In both the male and female brains, amyloid deposits abounded, as expected in Alzheimer’s disease – but they did not have the disease as such.

As for tau tangles, there were noticeably fewer of them in the female brain. It is believed that tau has a stronger effect on cognitive state, so it can be assumed that the woman retained a clear mind for a long time precisely because her mutation somehow prevented tau deposits. There were many tau tangles in the male brain, but they were unevenly distributed. In some areas, for example, in the entorhinal cortex, which is considered one of the main centers of memory, there were few tau deposits.

Gen APOE (coding protein apolipoprotein E) and the gene RELN (coding protein reelin) work differently in the adult brain: APOE active everywhere RELN – only in some places. Therefore, most likely, there is such a difference in the accumulations of tau protein: an anti-alzheimer’s variant APOE protects the whole brain from them, and the anti-alzheimer’s variant RELN – only those zones where it is active. What RELN prevents accumulation of tau protein, has been shown in experiments with mice that were predisposed to tau tangles: if in a mouse RELN there was a corresponding mutation, tau tangles did not appear in them.

You can try to find drugs that mimic the effect of mutant APOE and RELN – it is quite possible that they will help not only patients with hereditary Alzheimer’s disease, but also patients with the more common sporadic form. At the same time, one cannot ignore the problems regarding beta-amyloid and beta-amyloid plaques. Although tau tangles seem to be more strongly associated with cognitive decline (tau protein accumulates in other dementias as well), it is beta-amyloid that is being discussed as the main target for drugs that should slow down Alzheimer’s disease. However, all efforts to create such drugs end either with outright failure, or with relative success accompanied by serious side effects. It is possible that beta-amyloid deposits are only a symptom of other processes that are the true cause of the disease, and in order to create an effective anti-alzheimer’s drug, you need to focus more attention on something else – for example, on tau protein, on cholesterol metabolism or on special enzymes that regulate the activity of a large number of proteins in the brain.