Investigating the role of the calcium-regulating protein calpain in early Alzheimer’s disease

Research project:  Investigating calpain as a key mediator of Aβ-induced calcium dysregulation and synaptotoxicity in human neurons

Lead Investigator: Dr Ksenia Kurbatskaya
Institution: University of Southampton 
Grant type: Junior Fellowship
Duration: 36 months
Amount:  £195,525

Why did we fund this project?

Comments from members of our Research Network:

“Just the sort of talented researcher we should support for the future. A good application with original work with living tissue from a collaborative neurosurgical unit in a highly respected and supportive university department.”

“I think this would be an interesting project, of great use to the Alzheimer's Society and I support the purpose.”

“Very interesting hypothesis. Working with live human tissue which increases the relevance of the research.”

What do we already know?

Researchers believe that finding and understanding the earliest changes to the brain in Alzheimer’s disease will be very important when it comes to finding effective treatments. Currently it is believed that loss of the connections between brain cells, called synapses, could be one of the first things to happen in the disease process.

The presence of calcium is important for synapses to function correctly.  The amount of calcium coming in and out of the cell has to be tightly regulated and kept in a perfect balance. This process is regulated by types of proteins called receptors, which are found on the cell surface. 

Previous research has suggested that toxic clumps of amyloid protein – a key hallmark of Alzheimer’s disease – appear to affect the balance of calcium in the cell, leading to damage to synapses. Work in animals has shown that a protein called calpain also appears to be important to this process. Calpain helps to regulate other proteins in the cell, including the receptors that control the calcium levels. In the animal models, amyloid clumps cause the calpain to become overactive and disrupt the function of these receptors. Calpain also appears to affect the function of another important protein in the Alzheimer’s disease process, tau. 

What does this project involve?

Dr Kurbatskaya aims to understand whether the effect of amyloid on calpain is the same in people as it is in animals. The team will use adult human brain cells from live donors that have been surgically removed during other procedures. They will expose these cells to toxic forms of amyloid and use a variety of techniques study the effects that this has on calpain, calcium and its receptors and the tau protein. 

The team will also use cells donated by people with Alzheimer’s disease to see if blocking calpain in these cells can prevent damage to synapses. 

How will this benefit people with dementia?

This project will build on previous animal work to to uncover the causes of the earliest Alzheimer’s disease-related changes in human brain cells. It will also shed light on whether calpain could be a suitable target for future treatments for the condition. As there are some drugs being developed that already target calpain, this could potentially reduce the amount of time taken for a suitable drug to be brought to the people that need it. This ‘repurposing’ approach is an important part of our Drug Discovery programme. 
 

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