Can blocking the Dkk3 protein prevent the loss of connections between brain cells?

Research project: The role of the Wnt antagonist Dkk3 in Amyloid-plaque pathogenesis

Lead Investigator: Professor Patricia Salinas
Institution: University College London  
Grant type: Project Grant 
Duration: 36 months
Amount: £342,887

Why did we fund this project?

Comments from members of our Research Network:

'In the past I have monitored projects concerned with studying both the role of Wnt and Dkk so I am particularly interested to hear that the connection between them is to be studied here.'

'Sounds as though this could produce another piece of the jigsaw.'

'Building on other important research.'

What do we already know?

Neurons in the brain are connected across gaps called synapses. The neurons need these synapses in order to function correctly. Research indicates that synapse loss is one of the earliest changes in Alzheimer's disease and could lead to the death of neurons. 

Large, toxic clumps of a protein called amyloid are found in the brain in people with Alzheimer's disease. As there are fewer synapses around these large amyloid clumps, researchers believe that something within the plaques could be toxic to the synapses. 

Synapses are maintained by a protein known as Wnt.  The presence of another protein called Dkk1 stops Wnt from doing its job properly. Research by Professor Salinas indicates that the amyloid protein might cause an increase in the amount of Dkk1. This increase in Dkk1 could be blocking Wnt and therefore have a knock-on effect on the synapses. 

What does this project involve?

Professor Salinas and her team are going to investigate the role of a similar protein to Dkk1, called Dkk3. The Dkk3 protein is produced by neurons in the brain and also blocks Wnt. Increased Dkk3 levels lead to the loss of brain cells in the hippocampus (the brain's memory centre) in mice. The research team believes that Dkk3 might gather around the large amyloid plaques and lead to damage to synapses. 

The team will investigate the role of Dkk3 in the brain by adjusting the levels of the protein in animals that show signs of Alzheimer's. They will also examine Dkk3 and amyloid in brain tissue donated by people. This includes using state-of-the-art imaging techniques in order to view the microscopic synapses. The researchers will investigate whether blocking Dkk3 has any effect on the amyloid plaques or can prevent the loss of synapses. 

How will this benefit people with dementia?

Drugs that have targeted the amyloid protein directly have largely failed in clinical trials. Therefore researchers are looking for new ways to prevent brain cell loss in Alzheimer's. This project will add to our understanding of the role of the Wnt and Dkk proteins in the brain and could uncover potential avenues for the development of future treatments. 
 

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