Research team identifies early cellular disorder in Alzheimer's disease

Overactive nerve cells in certain areas of the brain are considered an early symptom of Alzheimer's disease. For the first time, a team from the Munich Technical University (TUM) was able to elucidate the causes and mechanisms of this initial and important step.

Glutamate cannot be removed quickly enough

Overactive nerve cells in certain areas of the brain are considered an early symptom of Alzheimer's disease. For the first time, a team from the Munich Technical University (TUM) was able to elucidate the causes and mechanisms of this initial and important step. The activating neurotransmitter glutamate cannot be removed quickly enough and thus strengthens the pathological excitation of nerve cells. This disorder may be decisive for the limited learning and memory ability of patients.

There are large clumps of the protein beta-amyloid in the brains of Alzheimer patients who are already displaying symptoms. Many therapeutic approaches are aimed at removing these clumps. So far, however, attempts to do this have not been very successful.

"The decisive factor is that we detect and treat the disease much earlier. Our starting point was, therefore, the overactive nerve cells, which occur very early - and long before the patient suffers from memory loss," explains Prof. Arthur Konnerth, Senior Professor of Neuroscience at the TUM. Overactivation constantly leads to false signals in neighboring cells, thus disrupting signal processing.

Beta-amyloid blocks glutamate reuptake

Konnerth, together with his doctoral student Benedikt Zott and the entire team, was able to discover the cause, the trigger and possible new therapeutic targets for this early disorder in the brain. The study was published in the journal Science.

As the researchers found out, glutamate was present for too long in very high concentrations in the synaptic cleft of the overactive nerve cells. They were able to show that the transport of the brain messenger substance was disturbed in these nerve cells. The reason for this was beta-amyloid molecules that blocked the nerve cell membranes for the transport of glutamate. They used both beta-amyloid molecules from patient samples and mouse models to detect this mechanism - with the same result.

A new possibility for the earliest possible therapeutic approach

The team found of great interest that this blockade was already triggered by an early soluble form of beta-amyloid and not by the clumped plaques. Beta-amyloid occurs in different forms: it is formed as a single molecule and then forms soluble two-constructs (dimers), which later form long chains that form the plaques. In the case of glutamate blockade, the dimers were the triggers.

"Our data provide clear evidence of a direct toxic effect of a particular beta-amyloid form: the dimers. We were even able to explain this mechanism," said Benedikt Zott, lead author of the study. The researchers now want to use this knowledge to further improve their understanding of the cellular causes of the development of Alzheimer's and to use this knowledge to develop therapeutic strategies that start early in the course of the disease.

Source:
Benedikt Zott, Manuel M. Simon, Wei Hong, Felix Unger, Hsing-Jung Chen-Engerer, Matthew P. Frosch, Bert Sakmann, Dominic M. Walsh, Arthur Konnerth, A vicious cycle of b amyloid-dependent neuronal hyperactivation, Science, August 9, 2019; DOI: 10.1126/science.aay0198
https://science.sciencemag.org/content/365/6453/559

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