Protein pairing linked to brain cell loss
Scientists at Heidelberg University, led by neurobiologist Prof. Dr. Hilmar Bading, have identified a molecular mechanism that appears to act as a “death switch” in Alzheimer’s disease. In collaboration with researchers at Shandong University, the team found that a toxic interaction between two proteins drives nerve cell damage and cognitive decline in a mouse model of the disease.
The key players are the NMDA receptor and the TRPM4 ion channel. NMDA receptors are critical for communication between neurons and support learning and memory when functioning at synapses. However, when they bind with TRPM4 outside synapses, their behavior changes. The resulting NMDAR/TRPM4 complex forms what researchers describe as a harmful “death complex” that damages and ultimately kills brain cells.
Blocking the toxic interaction
The study found that this neurotoxic complex appears at significantly higher levels in Alzheimer’s mice than in healthy controls. To interrupt the process, researchers used a compound known as FP802, developed by Prof. Bading’s team.
FP802 is classified as a “TwinF Interface Inhibitor.” It targets the specific interface where NMDA receptors and TRPM4 connect, preventing them from forming the damaging complex. By binding to this interaction site, the compound effectively disrupts the protein pairing.
Slower progression and preserved cognition
In treated mice, the results were notable. According to Dr. Jing Yan, formerly of Heidelberg University and now affiliated with FundaMental Pharma, disease progression slowed significantly. The animals exhibited reduced synapse loss and less structural and functional damage to mitochondria, which are vital for cellular energy production.
Importantly, treated mice maintained learning and memory abilities to a much greater extent than untreated counterparts. Researchers also observed a reduction in beta-amyloid accumulation, one of the defining features of Alzheimer’s pathology.
A different therapeutic strategy
Unlike many existing approaches that focus on preventing amyloid formation or removing amyloid plaques, this strategy targets a downstream mechanism that leads to neuronal death. Prof. Bading explained that blocking the NMDAR/TRPM4 complex may interrupt a feedback loop that both kills neurons and promotes amyloid buildup.
Earlier studies from the same group showed that FP802 also demonstrated neuroprotective effects in models of amyotrophic lateral sclerosis, suggesting that this protein interaction may play a broader role in neurodegenerative disorders.
Path to clinical application
While the findings are promising, researchers caution that clinical application remains distant. Further pharmacological refinement, safety testing and human clinical trials are required before the compound could be considered for therapeutic use.
The study was published in Molecular Psychiatry and supported by organizations including the German Research Foundation, the European Research Council and the National Natural Science Foundation of China. Collaborative work with FundaMental Pharma is ongoing to advance FP802 toward potential future treatments.