Understanding the factors governing vascular and glymphatic water transport in the brain in health and disease

The brain's vasculature is highly specialised. It tightly regulates transfer of essential molecules and ions into the brain, constantly maintaining a carefully balanced extracellular milieu in which neurones and other brain cells can function properly. In many neurological diseases such as dementia, stroke and brain tumours, the brain's vasculature becomes dysfunctional, allowing molecules to enter the brain unimpeded, disrupting this tightly controlled neurochemical balance.

The transfer rate of water into and out of the brain is a common factor affected by disease. The correct regulation of water movement between different compartments of the brain is important for several reasons:

i) Even small changes in the distribution of water between cellular compartments can drastically affect the composition of extracellular fluid, and hence the ability of brain cells to function properly,

ii) Effective clearance and circulation of water in the brain is essential for removal of waste products such as amyloid-B, a protein which accumulates in brain's of people with Alzheimer's disease.

The importance of well-regulated water balance is becoming increasingly recognised. There is now a need to understand the biophysical factors that drive changes in vascular water exchange so that drugs can be developed to restore brain water homeostasis. Our lab has developed approaches to measure vascular water exchange using MRI and we have demonstrated these method can detect changes in water exchange associated with ageing, AD, and peripheral inflammation.

We now wish to use these techniques to study how changes to vascular proteins such tight junctions and aquaporins impact brain water balance, and how these changes impact brain health. This project will involve the use of knock out mouse models to determine the impact of specific genes on vascular and perivascular water exchange, then investigate the impact of abnormal water transport/movement in mouse models of Alzheimer's disease.