The brains of Alzheimer's patients who have already developed clinical symptoms contain large clumps of the protein beta-amyloid, known as plaques. Many therapeutic approaches focus on removing plaques, but such attempts have met with only limited success to date.

"It's crucial that we detect and treat the disease much earlier. We therefore focused on hyperactive neurons, which occur at a very early stage - long before patients develop memory loss," explains the senior author . As a consequence of hyperactivation, connected neurons in the circuits constantly receive false signals, leading to impairments in signal processing.

The research team succeeded in identifying the cause and trigger of this early disturbance in the brain. The discovery may open the way to new therapeutic approaches. The study appeared in the journal Science.

The researchers discovered that high concentrations of glutamate persisted too long in the synaptic cleft of hyperactive neurons. This was due to the action of beta-amyloid molecules, which blocked glutamate transport out of the synaptic cleft. The team tested the mechanism using beta-amyloid molecules from patient samples and by using various mouse models obtaining similar results with both approaches.

The team was also intrigued to discover that the neurotransmitter blockade was mediated by an early soluble form of beta-amyloid and not by the plaques. Beta-amyloid occurs initially as a single molecule form, or monomer, and then aggregates to double-molecule forms (dimers) and larger chains resulting, eventually, in plaques. The researchers found that glutamate blockade is caused by the soluble dimers.

"Our data provide clear evidence for a rapid and direct toxic effect of a particular beta-amyloid type, the dimers. We were even able to explain this mechanism," the first author of the study, outlined. The researchers now want to use this knowledge to further improve their understanding of the cellular mechanisms of Alzheimer's and, thus, to support the development of strategies for treatment at early stages of the disease.
https://www.tum.de/nc/en/about-tum/news/press-releases/details/35644/

https://science.sciencemag.org/content/365/6453/559