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UCL Researchers Unlock Key Mechanism Behind Brain Connectivity And Memory

Alzheimers-Research-UK-logoThe findings, published today in the journal Current Biology, shed light on the processes driving communication breakdown in the brain and identify a protein called Wnt as a key target in the development of new treatments for diseases like Alzheimer’s. The research is funded by Alzheimer’s Research UK, Parkinson’s UK, Wellcome Trust, Medical Research Council and the EU.

The breakdown of connections between nerve cells is an early feature of diseases like Alzheimer’s and is known to cause distressing symptoms like memory and thinking decline. Nerve cells are connected at communication points called synapses and the slow degeneration of these connections is an important area of study for researchers looking to develop new treatments to slow or stop Alzheimer’s. There is still a lot that researchers must learn about which biological processes are responsible for this breakdown and how they cause such damage in the brain.

To explore this critical process further, Prof Patricia Salinas and her team at UCL studied a molecular chain of events driven by a protein called Wnt. Wnt has an important role during brain development, but recent research has also suggested that disruptions in this process may be linked with Alzheimer’s. To unpick the role of the Wnt pathway in Alzheimer’s, Prof Salinas focused on a second protein called Dkk1, which is known to block the action of Wnt. Previous research has suggested that Dkk1 levels are higher in people with Alzheimer’s.

The team used mice in which the Dkk1 protein can be switched on, disrupting the action of Wnt and its downstream chain of events. To avoid any disruption to normal brain development driven by Wnt and Dkk1, the researchers waited until the mice were adults before switching on Dkk1 in an area of the brain important for the formation of new memories.

When they switched on Dkk1 in the adult mice, the researchers found the mice had memory problems, and that this coincided with disrupted communication between nerve cells. The mice also had fewer synapses between nerve cells, indicating a communication breakdown. However, when the researchers switched Dkk1 back off, the mice no longer had memory problems, the number of synapses returned back up to normal levels and communication between nerve cells was restored.

Prof Patricia Salinas, said:

“Synapses are absolutely critical to everything that our brains do. When these important communication points are lost, nerve cells cannot exchange information and this leads to symptoms like memory and thinking problems. The Wnt pathway is emerging as a key player in the regulation of the formation, maintenance and function of synapses, and we have provided strong evidence that the Wnt protein is also critical for memory. Understanding the role of Wnt in Alzheimer’s disease is an important next step, as there is potential we could target this chain of events with drugs. Preventing or reversing the disruptions in connectivity and communication between nerve cells in Alzheimer’s would be a huge step forward.”

Dr Simon Ridley, Director of Research at Alzheimer’s Research UK, said:

“This study in mice adds further weight to a growing body of evidence implicating Wnt and its related proteins to nerve cell connectivity and memory. By understanding mechanisms driving healthy nerve cells, we can best unpick what happens when these processes go so wrong. This research sets a solid foundation for future work to explore the role of Wnt in diseases like Alzheimer’s, and this biological process is already a key target being explored by expert teams in the Alzheimer’s Research UK Drug Discovery Alliance. Researchers are taking huge steps forward in their understanding of what happens in the brain in health and disease, and we must now capitalise on these discoveries to deliver effective treatments that can transform lives.”













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