Title: Exploring the pathophysiology of vascular dysfunction and pericyte loss in dementia
Funder: Alzheimer's Research UK

Abstract: There is overwhelming evidence that damage to cerebral blood vessels and reduced blood flow through the brain are strong contributors to disease onset and cognitive decline in people with dementia. Vascular insufficiency is not only the underlying cause of vascular dementia (VaD) but is increasingly recognised to contribute to disease progression in most patients with Alzheimer’s disease (AD), in whom reduced cerebral blood flow occurs up to 15 years before the onset of clinical symptoms. Pericytes, specialised cells within the walls of blood vessels, regulate blood flow and produce chemicals needed to maintain vascular structure and function. Pericytes degenerate within the brain in AD, causing accelerated disease progression and cognitive decline in animal models of the disease. I reported recently that pericyte loss in the human brain was strongly associated with reduced blood flow, elevated amyloid beta (Aβ) deposition, breakdown of the blood-brain barrier (allowing noxious chemicals to leak from the bloodstream into the brain tissue), and the APOE ε4 genetic risk marker, in people who died of AD. The timing and causes of pericyte loss in relation to disease onset and progression in humans remains unknown. I will be exploring this in studies on human post-mortem brain tissue and in animal and cell culture models. I have generated preliminary data indicating that a marker of pericyte death is elevated in cerebrospinal fluid taken by lumbar puncture from AD patients and is a strong predictor of disease status. I will undertake a comprehensive study to determine whether this and other vascular markers are reliable predictors of early disease in people who develop AD. I will explore novel potential drug targets to prevent pericyte loss and restore blood flow in preclinical disease models with a view to providing information needed to support the use of these interventions in human clinical trials.

Lay abstract: There is overwhelming evidence that damage to cerebral blood vessels and reduced blood flow through the brain are strong contributors to disease onset and cognitive decline in people with dementia. Vascular insufficiency is not only the underlying cause of vascular dementia (VaD) but is increasingly recognised to contribute to disease progression in most patients with Alzheimer’s disease (AD), in whom reduced cerebral blood flow occurs up to 15 years before the onset of clinical symptoms. Pericytes, specialised cells within the walls of blood vessels, regulate blood flow and produce chemicals needed to maintain vascular structure and function. Pericytes degenerate within the brain in AD, causing accelerated disease progression and cognitive decline in animal models of the disease. I reported recently that pericyte loss in the human brain was strongly associated with reduced blood flow, elevated amyloid beta (Aβ) deposition, breakdown of the blood-brain barrier (allowing noxious chemicals to leak from the bloodstream into the brain tissue), and the APOE ε4 genetic risk marker, in people who died of AD. The timing and causes of pericyte loss in relation to disease onset and progression in humans remains unknown. I will be exploring this in studies on human post-mortem brain tissue and in animal and cell culture models. I have generated preliminary data indicating that a marker of pericyte death is elevated in cerebrospinal fluid taken by lumbar puncture from AD patients and is a strong predictor of disease status. I will undertake a comprehensive study to determine whether this and other vascular markers are reliable predictors of early disease in people who develop AD. I will explore novel potential drug targets to prevent pericyte loss and restore blood flow in preclinical disease models with a view to providing information needed to support the use of these interventions in human clinical trials.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;STROKE