Developing new ways to study and test treatments for small vessel disease in vascular dementia

Research project: Disintegration of the cerebral matrisome: a central mechanism leading to small vessel disease and vascular cognitive impairment

Lead investigator: Professor Karen Horsburgh
Institution: University of Edinburgh
Grant type: Project Grant 
Duration: 48 months
Amount: £800,000 (this project is part of a joint funding call with Stroke Association and British Heart Foundation- Alzheimer's Society is funding £217,600 of this)

Why did we fund this project?

Comments from members of our Research Network:

'This is a measured but forceful approach to a problem area which is clearly worrying both patients and researchers.'

'This project is very relevant to Alzheimer's Society priorities regarding vascular disease.'

'The opportunity to use a new human platform (stem cells) and a new animal model, seems too good to miss - especially with such a strong interdisciplinary team.'

What do we already know?

Cerebral small vessel disease (SVD) causes the small blood vessels in the brain to stop regulating blood flow to the brain properly. It is a common cause of strokes and vascular dementia. We don't really understand what causes small vessel disease, making it difficult to develop treatments for it. 

An area of the brain called the neurovascular unit is responsible for controlling the blood supply to brain cells. This unit prevents harmful molecules from moving from the blood into the brain and controls the immune cells in the brain. The cells of the neurovascular unit are supported by a special scaffold called the extracellular matrix. Problems with this scaffold could stop the neurovascular unit from performing its important role properly. 

Several genetic changes that increase the risk of stroke have now been identified. This includes in a gene called COL4, which is important in the extracellular matrix. This adds to growing evidence that damage to this scaffold may lead to small vessel disease and vascular dementia. 

Creating 'models' of disease in the lab, using animals such as mice and lab-grown stem cells, are important for investigating how certain genes may cause disease. We still haven't worked out exactly what triggers small vessel disease, and more relevant models are needed to study this.

What does this project involve?

This project is looking at the effects of changes to the COL4 gene in different models, to understand exactly how they cause small vessel disease. 

The team have developed a new animal model that has the increased risk version of COL4, so they can study the onset and progression of stroke and how changes in the scaffolding matrix affect the function of the neurovascular unit. 

They are also looking at the effects of the gene in models of neurovascular unit cells, which they have developed from the stem cells of people with disease-related changes to COL4. Cellular models like these could be used to rapidly test new drugs for small vessel disease. 

This programme is bringing together experts in animal and human models, and specialists in stroke. This will allow the researchers to relate what they see in models to what they see in people with the condition, which will help identify targets for treatments. 

How will this benefit people with dementia?

Understanding what causes small vessel disease could help to identify new drug targets, and developing new models like these to test new drugs will speed up drug discovery. This will hopefully lead to new treatments which can either prevent or halt small vessel disease, which could delay the onset of some forms of vascular dementia. 

Studying how the disease progresses in animal models could also help to identify biological signals such as particular molecular changes or differences in memory and thinking that can be used to recognise the disease. 

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