Understanding how protein changes lead to reduced brain blood flow and increased dementia risk (PhD Studentship)

See glossary at bottom of page for definition of underlined words.

Summary 

Restriction in blood flow to the brain (hypoperfusion) is present in most Alzheimer’s disease (AD) patients and has also been shown to be a predictor of AD in patients that don’t show any observable symptoms. Two proteins, Vascular endothelial growth factor (VEGF) and brain derived neurotrophic factor (BDNF), are known to interact and may be involved in the onset of hypoperfusion and neurodegeneration in dementia. This research will use a series of biochemical techniques to characterise the interaction between VEGF and BDNF and its effects in dementia. Understanding how these proteins interact will lead to the production better drugs that can treat dementia.

What do we already know?

There is a substantial overlap between Alzheimer’s disease (AD) and vascular dementia (VaD).  A reduction in blood flow (known as hypoperfusion) is present in most AD patients and has also been shown to be a predictor of AD in asymptomatic patients with a family history of the dementia.

Vascular endothelial growth factor (VEGF) and brain derived neurotrophic factor (BDNF) are angioneurins: proteins that influence both neuronal and vascular cell functions including neuroprotection, the regulation of angiogenesis (appropriate growth and maintenance of blood vessels) and synaptic plasticity (forming new memories).  These proteins are therefore important in supporting proper brain function by maintaining appropriate blood flow to the brain, however the expression and functions of these proteins are altered in AD.

What is this research trying to find out?

VEGF and BDNF are known to interact, and this project aims to characterise these interactions in order to work out how they change in neurodegenerative diseases such as AD, VaD and dementia with Lewy bodies (DLB).  They hypothesise that the alterations in the expression and interactions of VEGF, BDNF, and their receptors contribute to hypoperfusion and neurodegeneration.

How will they do this?

Levels of VEGF, BEDF, and their receptors will be measured in post-mortem brain samples from healthy individuals and individuals diagnosed with AD and DLB.  The researchers will then use living neuronal cell lines – applying amyloid-β, ischaemic conditions or AD-associated mutations – to understand how the signalling pathways involved in the VEGF and BDNF interactions are altered in AD.   A range of biochemical techniques will be used for this, including cell culture, ELISA, western blotting, immunocytochemistry and qPCR.  The results from these experiments will aid interpretation of the VEGF and BDNF measurements from human post-mortem tissue.

Why is it important?

By understanding the underlying roles of VEGF and BDNF and the effect of their interaction in the initiation and progression of dementia, we may be able to develop better drugs to treat dementia.  For example, VEGF- or BDNF-related drugs to maintain cerebral perfusion, reducing ischaemic damage and promoting amyloid-β removal.

Glossary

Hypoperfusion – Decreased blood flow to an organ.
Asymptomatic – Showing no symptoms of a disease.
Neurotrophic factor – A peptide or small protein produced by neurones which increase the overall survival of other neurons.
Neurodegeneration – The death of cells in the brain (neurons). Neurodegeneration is a characteristic sign of dementia related diseases.
Receptors – A protein or cell component that is specifically designed to bind a small molecule or protein to elicit an effect.
Amyloid-β – Small peptides which aggregate to form amyloid plaques in Alzheimer’s disease. These plaques will eventually lead to the death of cells in the brain.
Ischaemic conditions – Ischemia is a restriction of blood supply to tissues.
Mutations – A mutation is a change in the DNA sequence that makes up a gene.
Cerebral perfusion – The passage of blood flow to the brain.

Further information

Please click here for more information about the work of Dr Shelley Allen-Birt