New Insights into Protein Complexes Responsible for Neuron Death in Alzheimer’s Disease

Recent research from Heidelberg University has uncovered a critical molecular mechanism that contributes to the progression of Alzheimer’s disease. Led by neurobiologist Prof. Dr. Hilmar Bading, the study, published in the journal Molecular Psychiatry, identifies a neurotoxic protein-protein complex as a key driver behind nerve cell demise and cognitive decline.

In collaborative experiments with scientists from Shandong University in China, the researchers utilized an Alzheimer’s mouse model to investigate the role of this complex, which consists of the NMDA receptor—a pivotal component in nerve cell signaling—and the TRPM4 ion channel. While NMDA receptors are essential for normal cognitive functions, their overactivation outside synapses, in conjunction with TRPM4, forms a deadly complex that damages neurons.

The team found that levels of the NMDAR/TRPM4 complex are significantly elevated in Alzheimer’s mice compared to healthy controls. They demonstrated that a novel compound, FP802, a TwinF Interface Inhibitor developed by the team, can break apart this complex. FP802 works by binding to the contact surface through which TRPM4 interacts with NMDA receptors, effectively dissolving the toxic assembly.

In experiments, treatment with FP802 markedly slowed disease progression in the mice. Cellular damage common in Alzheimer’s—such as synapse loss, mitochondrial dysfunction, and formation of amyloid-beta plaques—was notably reduced. Memory and learning abilities remained largely intact, indicating a neuroprotective effect.

This approach diverges from traditional therapies that target amyloid deposits directly, instead focusing on blocking downstream cellular pathways that lead to neuron death. Prof. Bading emphasized that this method may offer a new therapeutic avenue for neurodegenerative diseases, not only for Alzheimer’s but also for conditions like ALS, where similar complexes are involved.

Although promising, the researchers acknowledge that significant work remains before clinical application. Upcoming steps include extensive pharmacological testing, toxicity assessments, and human trials. The team is working closely with biotech firm FundaMental Pharma to optimize FP802 for potential human use.

This discovery underscores the importance of understanding molecular interactions within neurons and opens avenues for developing treatments aimed at preserving neural integrity in degenerative diseases.