Direct toxic action of beta-amyloid identified

August 09, 2019

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 Professor Arthur Konnerth, Hertie Senior Professor of Neuroscience at the TUM. As a consequence of hyperactivation, connected neurons in the circuits constantly receive false signals, leading to impairments in signal processing.

Together with his doctoral student Benedikt Zott and the entire research team, Konnerth 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.

Beta-amyloid blocks glutamate re-uptake

Neurons use chemicals called neurotransmitters to communicate with each other. Glutamate, one of the most important of these chemicals, serves to activate connected neurons. Glutamate is released at the connecting site between two neurons, called synapse, and than rapidly removed to allow the transmission of the next signal. This removal involves so-called active pump molecules as well as a passive transport of glutamate along nearby membranes.

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.

Indication for treatment strategies at early stages

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," as Benedict Zott, 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.
-end-
Download high-resolution images:

https://mediatum.ub.tum.de/1516971

Further information:

Professor Arthur Konnerth is a member of the cluster of excellence "SyNergy - Munich Cluster for Systems Neurology", which studies how neurological diseases such as Alzheimer's disease and multiple sclerosis develop. Because the nervous system is extremely complex, the development of neurodegenerative diseases is influenced by numerous processes. A new interdisciplinary approach, system neurology, lies at the heart of the Munich research. The cluster has been funded by the Excellence Initiative since 2012. In addition to the joint applicants TUM and LMU, the German Center for Neurodegenerative Diseases, Helmholtz Zentrum München and the Max Planck Institutes of Biochemistry, Neurobiology and Psychiatry are also involved in SyNergy.

Profile of Professor Arthur Konnerth
http://www.professoren.tum.de/en/konnerth-arthur/

Institute of Neuroscience of the TUM
http://www.ifn.me.tum.de/new/konnerth.php

Website of the SyNergy Cluster
https://www.synergy-munich.de/index.html

Contact:

Prof. Arthur Konnerth
Hertie Senior Professor of Neurosciences
Institute of Neuroscience of the Technical University of Munich
Tel.: +49-89-4140-3350
Email: arthur.konnerth@tum.de

Technical University of Munich (TUM)

Related Science Articles from Brightsurf:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.

Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.

Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.

Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.

World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.

PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.

Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.

Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.

Read More: Science News and Science Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.