Researchers identify neurotoxic protein complex and a pharmacological inhibitor that opens new perspectives for developing effective therapies
A research group led by neurobiologist Prof. Dr. Hilmar Bading at Heidelberg University has identified a molecular process that appears to play a major role in the advancement of Alzheimer’s disease.
Working closely with scientists from Shandong University (China), the team used an Alzheimer’s mouse model to show that a harmful interaction between two proteins triggers the death of nerve cells in the brain, which in turn contributes to worsening memory and thinking problems. The researchers say this discovery may open new opportunities for creating more effective therapies.
The harmful protein combination, previously recognized in earlier studies, is formed by the NMDA receptor and the TRPM4 ion channel. NMDA receptors help transmit signals between nerve cells and are located on the cell surface, both at synapses and in surrounding areas. These receptors respond to the neurotransmitter glutamate, which acts as a chemical messenger in the brain.
Although the activity of synaptic NMDA receptors is essential for keeping nerve cells healthy and supporting normal cognitive function, the presence of TRPM4 causes extrasynaptic NMDA receptors to become toxic. Working together, these proteins form what Hilmar Bading describes as a “death complex,” a structure that can severely damage neurons or cause them to die. Bading leads the Institute of Neurobiology at Heidelberg University’s Interdisciplinary Center for Neurosciences (IZN).
A Novel Inhibitor That Breaks the Toxic Interaction
The researchers report that Alzheimer’s mice carry this neurotoxic NMDAR/TRPM4 complex at much higher levels than healthy mice. To explore its role further, the team tested a new compound known as FP802, described as a “TwinF Interface Inhibitor” and originally identified by Prof. Bading and his colleagues at the IZN. Their results show that FP802 can interfere with the harmful interaction between these proteins and highlight its central involvement in the worsening of cognitive symptoms.
In experiments on a mouse model, they succeeded in breaking the deadly protein-protein complex apart using this neuroprotective molecule. FP802 binds to the so-called “TwinF” contact surface through which TRPM4 interacts with NMDA receptors, thereby blocking the physical interaction between the two proteins and dissolving the complex.
“In Alzheimer’s mice treated with the molecule, disease progression was markedly slowed,” states Dr Jing Yan, a researcher in Prof. Bading’s team who now works at FundaMental Pharma, a biotech offshoot of the IZN’s Institute of Neurobiology.
Typical cellular changes due to Alzheimer’s disease – including the loss of synapses and structural and functional damage to mitochondria, the powerhouses of the cell – developed only to a limited extent or not at all, the scientists report. Cognitive abilities such as learning and memory remained largely preserved. In addition, the characteristic formation of beta-amyloid deposits in the brain was significantly reduced.
A New Direction for Alzheimer’s Therapeutics
According to Prof. Bading, this approach fundamentally differs from previous treatment strategies for Alzheimer’s disease. “Instead of targeting the formation or removal of amyloid from the brain, we are blocking a downstream cellular mechanism, the NMDAR/TRPM4 complex, that can cause the death of nerve cells and – in a disease-promoting feedback loop – promotes the formation of amyloid deposits,” states the Heidelberg neurobiologist.
In prior studies, the team was able to demonstrate comparable neuroprotective effects of the TwinF Interface Inhibitor FP802 in disease models for amyotrophic lateral sclerosis (ALS), in which the NMDAR/TRPM4 complex also plays a role.
The researchers therefore believe they have found in the novel inhibitor a potentially widely applicable pharmacological principle that could slow or even stop the progression of neurodegenerative diseases like Alzheimer’s and ALS. Prof. Bading reports, however, that a prospective clinical application is still a long way off.
“The previous results are quite promising in the preclinical context, but comprehensive pharmacological development, toxicological experiments, and clinical studies are needed to realize a possible application in humans,” stresses the scientist. In close cooperation with FundaMental Pharma, the neuroprotective molecule FP802 is to be optimized for this in the coming years.
Reference: “The NMDAR/TRPM4 death complex is a major promoter of disease progression in the 5xFAD mouse model of Alzheimer’s disease” by Jing Yan, Xiaohui Yang, Guilin Li, Omar A. Ramirez, Anna M. Hagenston, Zhe-Yu Chen and Hilmar Bading, 26 August 2025, Molecular Psychiatry.
DOI: 10.1038/s41380-025-03143-5
The research was funded by the German Research Foundation, the European Research Council, the former Federal Ministry of Education and Research, the National Natural Science Foundation of China, and the east Chinese province of Shandong.
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