Neurodegeneration: Nervous feedback congestion

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Neurodegeneration: Nervous feedback congestion
Neurodegeneration: Nervous feedback congestion

Nervous Feedback Congestion

Patients with Down syndrome suffer from the loss of some brain cells from birth, while neurons in Alzheimer's patients often die off like flies in old age. Despite all the differences: Both neurodegenerative diseases seem to have a common basis.


A nerve cell is the opposite of an antisocial loner if need be – which differs not a little from a single liver cell in culture or a blood cell. The liver cell, for example, also carries out its digestive and detoxification duties on its own, just as a red blood cell also transports oxygen in isolation, as if nothing had happened. A lonely nerve cell, however, simply makes no sense: it can only do what it is there for together in networked cooperation with its peers.

Communication is therefore everything in the realm of neurons - if it is missing, it is better to give up immediately. The structural principle of the central nervous system also follows this logic from the very beginning of life: Although countless nerve cells are formed, many of them die off again if they cannot meaningfully integrate into the network. The individual nerve cells negotiate independently and among themselves which neurons are destined to die early.

Generally speaking, the closer and more functional the contact between two neurons that meet, the less reason there is to let a partner die. Neuron X thus signals good contacts to the connecting neuron Y with the help of secreted growth factors, the so-called neurotrophins, which include NGF (erve growth f actor) counts. Molecules like NGF bind to certain receptors on Y, but are also taken up by the nerve and transported from here to the cell nucleus, where they tell the command center that there is no reason for cellular suicide at this time: we are in contact – everything is fine.

This works fine until something goes wrong. And a lot can go wrong in this signal chain, as two research groups are now examining once again. They de alt with a mouse disease that triggers neurodegeneration in the brain and is considered a model for Down's syndrome in humans. In this chromosomal disease, each cell contains three copies of chromosome 21 instead of two.

Of course, this entails some problems, which - that much is clear - mostly have to do with the overproduction of the many proteins whose genes are present one too many on the extra chromosome. In the mouse analogue of Down syndrome (trisomy 16), which Ahmad Salehi and colleagues from Stanford University investigated, body cells with their several hundred additional gene copies also produce a whole range of proteins in excessive concentrations. Salehi and co examined the consequences of this overproduction on brain nerves - and after their investigations they were amazed to find that from the large circle of possible culprits there was only one main suspect: the overproduced protein app (amyloid precursor protein) [1]. It is particularly notorious as a mysterious player in Alzheimer's disease.

In trisomy 16 mice, the overly numerous app mob forms bad company for other proteins in nerve cells, as Salehi and colleagues recognized. In neurons of brain regions that are responsible for cognitive processes, certain fragments of the mass-produced App proteins fatally accumulate in precisely those transport vesicles that are responsible for the intracellular dispatch of the neurotrophin NGF transmitted by neighboring cells. The nerve cell recognizes this and stops local traffic – which means that the NGFs traveling with you no longer reach their cell nucleus terminal station. As a result, the neuron does not receive the feedback that it is in good contact with the neighboring neurons – and because it is supposedly superfluous, it soon initiates its cellular suicide.

Susan Dorsey from the University of Maryland and her team are also interested in the neurodegeneration in the mouse brain triggered by trisomy 16 - and they also find the cause in a disorder of neurotrophin communication [2]. However, they discovered another cause that is produced excessively in the hereditary mice: the neurotrophin receptor variant TrkB. T1. It has also been known to researchers since the year 2000: At that time, scientists recognized that brains with neurons that have too many of these receptors generally have poorer long-term memory performance.

Also, according to Dorsey and Co, the excess of TrkB. T1 in their mouse model makes neurons think, despite actually good neurotrophin signal strength, that they are poorly connected to neighboring cells - with the usual consequences, the voluntary separation from the own neural existence. Neuron degeneration actually dropped significantly to normal when the scientists genetically engineered the number of TrkB. T1 receptors back to normal.

As with Salehi's work, the alarm bells of Alzheimer's researchers are also ringing with Dorsey's findings - because in Alzheimer's disease not only does an abnormal amount of the aforementioned APP play a role, but also an increased number of certain TrkB. T1-like neurotrophin receptors. The early stages of Alzheimer's disease are also revealed by increased neuronal degeneration. The results of Salehi, Dorsey and their colleagues therefore lead to the conclusion that the neurotrophin communication pathway is also disrupted in Alzheimer's patients. The researchers hope that the hitherto underestimated Achilles' heel, the intracellular transport of nerve signals, could perhaps be strengthened and protected with drugs in the (unfortunately still distant) future - and with them all those whose nerve cells may one day no longer be able to talk to each other threaten lonely.

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