Harmful Proteins: Not just typical Alzheimer's accumulations of beta-amyloid proteins are toxic to the brain. Even early, not yet coated versions of these substances can develop deleterious effects, as the study now shows: they prevent the removal of an important glutamate neurotransmitter – and thus trigger neuronal hyperactivity. This pathological excitation of nerve cells is one of the very early symptoms of dementia.
Alzheimer is one of the most common neurodegenerative diseases in the world. As a typical symptom of progressive destruction of brain cells, deposits of accumulated proteins can be found in the heads of patients: Instead of being broken down, so-called beta-amyloid proteins accumulate more and more. The resulting plaques are considered to be a possible driver of inflammatory processes, synaptic dysfunction and eventually cell death.
Therefore, many therapies investigated to date have focused on eliminating these clots – but far-reaching successes have not been achieved. "What is important is that we recognize and treat the disease much earlier," says Arthur Konnerth of the Technical University of Munich. In the search for alternative treatment approaches, the doctor and his colleagues around the first author, Benedict Zott, devoted themselves to the very early feature of this form of dementia.
Studies suggest that many Alzheimer's patients have markedly increased neuronal activity before the onset of memory loss, especially in the hippocampus and some regions of the cerebral cortex. But what is the reason? "The unanswered question is whether such a pooled beta-amyloid protein can cause cellular dysfunctions like hyperactivity," the researchers explain.
The key factor is glutamate
To find out, the team conducted experiments with Zott cells and experiments with mice. Rodents have been genetically modified to accumulate beta-amyloid proteins in the brain and Alzheimer's disease. He noted: Apparently, beta-amyloid proteins could actually play a role in over-activity in certain areas of Alzheimer's disease. Because these molecules interfere with the transport of messenger glutamate, as experiments have shown.
As a so-called neurotransmitter, glutamate is important for communication with neurons, activating nerve cells. This effect is developed by the messenger when released into the synaptic cleft between two neurons. To stop the effect, glutamate molecules must be transported back to the cell. This process takes place on the one hand actively through special pump molecules, on the other passively simple transport along the membranes.
Not only the plaques are harmful
Beta-amyloid proteins block nerve cell membranes, so glutamate cannot transfer so well back. As a result, glutamate remains for too long and at too high concentrations in the synaptic fissure – and this leads to excessive excitation of the nerve cell.
Key point: Not only the accumulated protein versions act on neurons in the hippocampus, but also the early, soluble forms. Thus, beta-amyloid is first formed in the brain as a unique molecule, then forms dimers and later long chains that form plaques. "Our data provide clear evidence of the direct toxic effect of the dimer," Zott reports.
A new approach to therapies?
Even before typical shrinkage occurs, beta-amyloid proteins develop, which can lead to deleterious effects in the brain: complicating glutamate removal. According to the researchers, this finding is consistent with the observation that certain drugs that interfere with the glutamate system appear to help counteract mental loss.
If these results can be confirmed, it would not only be possible to clarify the cause of overactive nerve cells in the brains of Alzheimer's patients. By deciphering this early disorder, new approaches to early dementia therapies may emerge, he hopes. (Science, 2019; doi: 10.1126 / science.aay0198)
Source: Technical University of Munich