A team led by neurobiologist Professor Hilmar Barding from Heidelberg University has identified a key molecular process that promotes the progression of Alzheimer’s disease. Working with researchers at Shandong University in China, scientists used a mouse model of Alzheimer’s disease to show that harmful protein interactions cause brain cell death and lead to cognitive decline. The findings suggest new possibilities for developing more effective treatments.
The deleterious protein interaction involves two previously studied components, the NMDA receptor and the TRPM4 ion channel. NMDA receptors play an important role in communication between nerve cells and are located on the cell surface both at synapses and in areas outside these junctions. These are activated by the important neurotransmitter glutamate.
When NMDA receptors function within synapses, they support neuron survival and help maintain cognitive function. However, when TRPM4 interacts with NMDA receptors outside the synapse, its behavior changes in a deleterious direction. Together, they form what researchers call a “death complex” that can damage and kill nerve cells, says Hilmar Barding, director of the Institute of Neurobiology at the Interdisciplinary Center for Neuroscience (IZN) at Heidelberg University.
Experimental drug breaks the link between toxic proteins
The study found that this neurotoxic NMDAR/TRPM4 complex was expressed at much higher levels in Alzheimer’s disease mice than in healthy mice. To target this mechanism, the researchers used a compound called FP802, a “TwinF interface inhibitor” previously developed by Professor Bading’s team.
In mouse experiments, FP802 successfully inhibited the interaction between TRPM4 and NMDA receptors. This molecule binds to the “TwinF” interface where the two proteins connect, preventing interaction and effectively disassembling the toxic complex.
Slows disease progression and preserves memory
“In Alzheimer’s disease mice treated with this molecule, the progression of the disease was significantly slowed,” said Dr. Jing Yang, previously part of Professor Barding’s team and now at Fundamental Pharma. The treated animals had far less cell damage typical of Alzheimer’s disease. This includes reducing the loss of synapses and reducing structural and functional damage to mitochondria, the power source of cells.
Importantly, learning and memory abilities are largely intact. The researchers also observed a significant reduction in the buildup of beta-amyloid in the brain, a hallmark of Alzheimer’s disease.
New treatment strategies beyond amyloid
Professor Bading emphasizes that this approach is different from traditional approaches to Alzheimer’s disease. “Rather than targeting the formation or removal of amyloid from the brain, we are blocking the NMDAR/TRPM4 complex, a downstream cellular machinery that can drive the formation of amyloid deposits in a feedback loop that causes neuronal cell death and promotes disease,” he explains.
Previous work by the same team showed that FP802 also had neuroprotective effects in models of amyotrophic lateral sclerosis (ALS), another neurodegenerative disease that involves the same protein interactions.
Future possibilities and next steps
Researchers believe this inhibitor could be a widely applicable strategy to slow or stop neurodegenerative diseases such as Alzheimer’s disease and ALS. However, Professor Beding warns that clinical use is still a long way off. “Although the results to date are very promising in a preclinical setting, comprehensive pharmacological development, toxicological experiments, and clinical studies are required to realize potential human applications,” he says.
Efforts are currently underway in collaboration with FundaMental Pharma to further refine FP802 for potential therapeutic applications.
Funding and publication
This research received support from the German Research Foundation, the European Research Council, the former Federal Ministry of Education and Research, the National Natural Science Foundation of China, and East China’s Shandong Province. The research results were published in a magazine molecular psychiatry.
