Research

By 2040, 1.4 million people in the UK alone are expected to be living with dementia, for which we have no treatment. The most common dementia, Alzheimer’s Disease (AD), is associated with reduced brain blood flow, resulting in an inability to supply the required energy to active neurons. This may lead to neurons dying, and impairment of mental processes such as memory.  Using mouse models of dementia, we are investigating whether driving vascular oscillations can have disease modifying effects, with the aim of highlighting novel therapeutic approaches for dementia.

Cardiovascular disease is a risk factor for dementia. By combining models of Alzheimer's disease with a novel model of atherosclerosis we are studying how cardiovascular disease might affect the progression and severity of Alzheimer's disease. Experimental approaches used in this research include high-resolution 2-photon imaging, wide-field imaging approaches, electrophysiology, behavioural testing and immunohistochemistry.

Using optogenetics, optical imaging, electrophysiology, and pharmacological approaches we are investigating the role that inhibitory interneurons play in the control of brain blood flow. This research helps us to understand how the brain functions and may highlight cell types which become dysfunctional in diseases in which deficits in brain blood flow occur, such as Alzheimer's disease and epilepsy. By understanding the cellular underpinnings of brain blood flow regulation, we will be able to better interpret commonly used functional imaging approaches such as fMRI BOLD.

To ensure that neurons receive the energy that they need when active, neurovascular coupling ensures that neural activity is accompanied by changes in brain blood flow, bringing oxygen and glucose to the active brain area. We are investigating how various behaviours and brain states regulate the different blood vessels within and surrounding the brain. For example, behaviour regulates dural and cerebral vessels, with spontaneous locomotion inducing dural vessel constriction as well as increasing stimulus-evoked brain blood flow responses. Investigating the function of different types of blood vessels associated with the brain will allow us to better understand the role of the neurovascular unit in health and disease, and may indicate potential targets for vascular-based therapeutic interventions for neurodegenerative diseases.

The development of therapeutics to prevent or slow down the progression of dementia is desperately needed. Heart disease and other vascular diseases have long been associated with an increased risk of developing dementia later in life. Therefore, targeting shared disease mechanisms in both heart diseases and dementia could be an important therapeutic strategy. One such shared mechanism is inflammation. We have previously found elevated inflammatory molecules in the brains of mice with heart disease. Dr Shabir's research aims to target these molecules to prevent brain damage/improve brain health and reverse or stabilise cognitive decline. If successful, this could provide a strong foundation for clinical studies involving the repurposing of such drugs (currently clinically licensed for arthritis) in the treatment or prevention of dementia. Dr Shabir's work is supported by a BHF Immediate Postdoctoral Fellowship.

How changes in cerebral perfusion during normal ageing and neurodegenerative diseases impact cognitive function remains incompletely understood. An important unanswered question is: when does oxygen insufficiency occur in middle age, and why and when does this become problematic for human health? To address these questions, Dr Christie is exploring the use of an MRI contrast agent, hyperpolarised xenon gas, to quantify changes in brain oxygen availability. She will test the hypothesis that oxygen is the rate limiting factor for neuronal computation. Building on her previous work investigating how astrocytes regulate oxygen homeostasis in the brain, Dr Christie's current research focuses on translating novel neuroimaging methods for use in humans. Dr Christie's work is supported by a Wellcome Career Development Award.