Summary: Scientists have discovered that a toxic complex between NMDA receptors and TRPM4 channels causes neuronal death in Alzheimer’s disease. Using a new molecule called FP802, the researchers were able to disrupt this complex in mice, preventing cognitive decline, synapse loss, and mitochondrial damage.
The treatment also reduced the accumulation of amyloids, suggesting that it may offer broader protection than current treatments. While the results are still preliminary, they open up a promising new avenue for treating Alzheimer’s and other neurodegenerative diseases such as ALS.
Key facts
- Identified toxic complexes: The NMDAR/TRPM4 complex causes neuronal death and promotes the progression of Alzheimer’s.
- Candidate drug: FP802 disrupted the complex in mice, preserving memory, synapses, and mitochondrial health.
- New method: It targets downstream cell death mechanisms rather than directly removing amyloid plaques.
Source: Heidelberg University
A research team led by neurobiologist Prof. Dr. Hilmar Bading at Heidelberg University has discovered a molecular mechanism that plays a key role in the progression of Alzheimer’s disease.
In joint experiments with researchers from Shandong University (China), the team used a mouse model of Alzheimer’s disease to demonstrate that a neurotoxic protein-protein complex is responsible for the death of nerve cells in the brain and subsequent cognitive decline.
According to scientists, this discovery opens new avenues for the development of effective treatments.
The protein-protein complex, known from previous studies, is formed by the NMDA receptor and the TRPM4 ion channel. NMDA receptors, involved in signal transmission between neurons, are located on the cell surface and are present both at synapses and outside these contact points.
They are activated by a biochemical messenger, the neurotransmitter glutamate. Although activation of synaptic NMDA receptors in the brain is important for the survival of nerve cells and maintaining cognitive abilities, TRPM4 confers toxic properties to extrasynaptic NMDA receptors.
Hilmar Beding, head of the Institute for Neurobiology at the Interdisciplinary Center for Neuroscience (IZN) at Heidelberg University, explains that together they form a ‘death complex’ that can damage and even kill nerve cells.
Research shows that the neurotoxic NMDAR/TRPM4 complex is present in much higher concentrations in mice with Alzheimer’s disease than in healthy animals.
Utilizing the novel pharmaceutical compound FP802, a “TwinF interface inhibitor” identified in earlier research by Professor Bading and his team at the Interdisciplinary Center for Neurosciences (IZN), the international research team has confirmed that the NMDAR/TRPM4 complex is a major contributor to the progression of cognitive decline.
In experiments using a mouse model, they were able to break down the lethal protein-protein complex using this neuroprotective molecule. FP802 binds to an interface called “TwinF,” allowing TRPM4 to interact with NMDA receptors, blocking the physical interaction between the two proteins and dissolving the complex.
“In mice with Alzheimer’s that were treated with the compound, the progression of the disease was markedly delayed,” says Dr. Jing Yan, a member of Professor Bading’s research team who is now employed at FundaMental Pharma, the biotechnology branch of the IZN Institute of Neurobiology.
Common cellular changes caused by Alzheimer’s disease, including loss of synapses and structural and functional damage to mitochondria (the cell’s powerhouses), occur only to a limited extent or not at all, scientists report.
Cognitive skills, such as learning and memory, were largely preserved. Additionally, the characteristic formation of beta-amyloid deposits in the brain was significantly reduced. According to Professor Beding, this approach is fundamentally different from previous strategies for treating Alzheimer’s disease.
“Rather than focusing on the formation or clearance of amyloid in the brain, we targeted a downstream cellular process the NMDAR/TRPM4 complex which can lead to neuronal death and, through a disease-amplifying feedback loop, further drive the accumulation of amyloid deposits,” explained the Heidelberg-based neurobiologist.
In previous studies, the team was able to demonstrate similar neuroprotective effects of the TwinF interface inhibitor FP802 in disease models of amyotrophic lateral sclerosis (ALS), in which the NMDAR/TRPM4 complex also plays a role.
The researchers believe they have discovered a pharmacological principle in the new inhibitor that has broad potential to slow or stop the progression of neurodegenerative diseases such as Alzheimer’s and ALS. However, Professor Beding reports that there is still a long way to go before it can be applied clinically.
“The above results are promising in a clinical context, but extensive pharmacological development, toxicological experiments and clinical studies are needed to achieve potential application in humans,” the scientists emphasize.
In close collaboration with FundaMental Pharma, the neuroprotective molecule FP802 will be optimized for this purpose in the coming years.
Funding: This research was funded by the German Research Council, the European Research Council, the former Federal Ministry of Education and Research, the National Natural Science Foundation of China, and Shandong Province, China. The results were published in the journal Molecular Psychiatry.
About this genetics and Alzheimer’s disease research news
Author: Ute Mueller-Detert
Source: Heidelberg University
Contact: Ute Mueller-Detert – Heidelberg University
Image: The image is credited to StackZone Neuro
Original Research: Open access.
“The NMDAR/TRPM4 death complex is a major promoter of disease progression in the 5xFAD mouse model of Alzheimer’s disease” by Hilmar Bading et al. Molecular Psychiatry
Abstract
The NMDAR/TRPM4 death complex is a key promoter of disease progression in the 5xFAD mouse model of Alzheimer’s disease.
Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by cognitive impairment and neuronal degeneration.
The formation of amyloid-β plaques and neurofibrillary tangles are the main morphological features of Alzheimer’s disease. However, the specific molecules responsible for the cell destruction caused by amyloid-β and tau proteinopathies in Alzheimer’s disease remain to be identified.
Here we used the 5xFAD mouse model of AD to investigate the role of a recently discovered death signaling complex that includes the extrasynaptic N-methyl-D-aspartate receptor (NMDAR) and transient receptor potential cation channel subfamily M member 4 (TRPM4).
The NMDAR/TRPM4 death complex is responsible for toxic glutamate signaling, which is linked to the pathogenesis of AD.
We found increased NMDAR/TRPM4 death complex formation in the brains of 5xFAD mice. This increase was blocked by oral administration of FP802, a small molecule inhibitor of the TwinF interface that can disrupt the NMDAR/TRPM4 death complex and thereby detoxify it.
Treatment with FP802 prevented cognitive decline in 5xFAD mice, as assessed using a battery of memory tests. Furthermore, it preserved the structural complexity of dendrites, prevented synapse loss, reduced the formation of amyloid-β plaques, and protected against pathological mitochondrial changes.
These results demonstrate that the NMDAR/TRPM4 death complex is a key promoter of Alzheimer’s disease progression by enabling a potentially self-sustaining pathological process initiated by amyloid β.
TwinF interface inhibitors offer a new therapeutic option and serve as an alternative or additional treatment to antibody-mediated clearance of amyloid β from AD brains.
