Hyperactive neurons in specific areas of the brain are believed to be an early perturbation in Alzheimer’s disease.
For the first time, a team from the Technical University of Munich (TUM) was able to explain the reasons and mechanisms underlying this early and therefore important neuronal dysfunction.
They found that the excitatory neurotransmitter glutamate persists for too long near active neurons.
This causes a pathological overstimulation of those neurons – most likely contributing critically to impaired learning and memory loss in Alzheimer’s patients.
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.
Forms of beta-amyloid
Toxic beta-amyloid is a distinguishing hallmark of Alzheimer’s disease. But not all forms of beta-amyloid are toxic. Brain cells, or neurons, make the protein in a simple form called a monomer. Monomer forms of beta-amyloid carry out essential jobs in brains cells.
However, in people with Alzheimer’s disease, beta-amyloid monomers cluster into oligomers, which can contain up to 12 monomers.
The formation of protein deposits is a typical feature of diseases in which a protein fails to fold properly into the shape necessary for it to do its job.
In Alzheimer’s disease, the oligomers continue to grow into longer shapes, and then eventually, they form much bigger deposits, or plaques.
At first, scientists thought that plaques were the most toxic form of beta-amyloid that produced symptoms of Alzheimer’s disease, such as loss of memory and thinking capacity.
However, due to growing evidence, an increasing number of experts are suggesting that the earlier oligomer stages of beta-amyloid are likely to be the most toxic to brain cells.
Synthetic peptide targets oligomers
The researchers designed the synthetic peptide alpha sheets to target beta-amyloid while it is at the oligomer-forming stage.
“This is,” says corresponding study author Valerie Daggett, who is a professor of bioengineering at UW, “about targeting a specific structure of [beta-amyloid] formed by the toxic oligomers.”
The study shows, she adds, that it is possible to devise synthetic peptide alpha sheets whose structures “complement” those of beta-amyloid as it assumes a toxic form, “while leaving the biologically active monomers intact.”
The process of making proteins in cells eventually produces molecules of diverse 3D shapes. The first stage of this involves folding the long chain into one of several basic shapes.
Prof. Daggett’s team had discovered one such basic shape — the alpha sheet — in earlier work in which they had simulated production of proteins on computers.
The recent study reveals that beta-amyloid oligomers adopt the alpha-sheet shape as they form longer clumps and plaques.
It also shows that the synthetic peptide alpha sheet binds only to beta-amyloid oligomer alpha sheets and that this neutralizes their toxicity.
Big drop in beta-amyloid oligomers
The team used traditional and state-of-the-art spectroscopes to watch how beta-amyloid progressed from monomers to oligomers to plaques in cultured human brain cells.
They also confirmed that oligomers were more harmful to brain cells than plaques. This finding supports studies that have found beta-amyloid plaques in the brains of people without Alzheimer’s disease.
The team showed that treating samples of brain tissue from a mouse model of Alzheimer’s disease with alpha sheets of synthetic peptide led to an 82 percent reduction in beta-amyloid oligomers.
In addition, treating the live mice with alpha sheets of synthetic peptide reduced their beta-amyloid oligomer levels by 40 percent within 24 hours.
The team also carried out experiments on another common model of Alzheimer’s disease, the worm Caenorhabditis elegans. These showed that treatment with alpha sheets of synthetic peptide was able to delay paralysis due to beta-amyloid.
Treated worms also showed less of the gut damage that develops when they feed on bacteria that produces beta-amyloid.
Finally, the researchers showed that it could be possible to use alpha sheets of synthetic peptide to test for levels of beta-amyloid oligomers.
Prof. Daggett and her team are already experimenting with new versions of synthetic peptide alpha sheets to find those that can neutralize beta-amyloid oligomers even more effectively.
“[Beta-amyloid] definitely plays a lead role in Alzheimer’s disease, but while historically attention has been on the plaques, more and more research instead indicates that amyloid beta oligomers are the toxic agents that disrupt neurons.” – Prof. Valerie Daggett
More information: Benedikt Zott et al, A vicious cycle of β amyloid–dependent neuronal hyperactivation, Science (2019). DOI: 10.1126/science.aay0198
Journal information: Science
Provided by Technical University Munich
