Interplay between brain endothelial cells and pericytes in brain health and disease

An emerging role of brain vasculature in the development and progression of human neurodegenerative diseases, particularly Alzheimer's disease (AD) and related dementias, has led to increasingly recognized importance of healthy blood vessels for normal brain functioning. Over the past decade, growing evidence supports that brain vascular dysfunctions occur early in AD and other dementing diseases, and might drive the first pathological steps towards dementia. In particular, brain capillaries, the smallest vessels accounting for ~85% of the total vessel length, were found to leak early, partly due to damage to pericytes. Pericytes are important cells wrapping around capillaries and maintaining vascular integrity. They were found to die early in AD and other neurological disorders. Protecting the brain from vascular leakage is therefore critical and we need to identify the specific factors which injure pericytes so that we can develop precise treatments. Another early feature of dementia is an excessive inflammation of brain vessels. Abnormal vascular inflammation correlates with the severity of brain damage and cognitive decline, as observed in patients with AD or other dementias. This project will identify how vascular inflammation can cause pericyte dysfunction and vice versa, and how these processes might be stopped using animal models and cell culture systems. The proposed study has three goals: The first goal is to work out the link between vascular inflammation, pericyte injury, and leaky brain vessels. I will investigate how vascular inflammation drives pericyte dysfunction and vascular disruption, as well as how pericyte dysfunction may also trigger vascular inflammation and subsequent vascular leakage. I will identify the specific factors involved in early vascular defects. The second goal is to grow brain vessels in a dish and study further the impact of inflammation on pericyte functions and vice versa. I will enhance or block specific inflammatory factors and investigate the effects on pericyte and vascular functions. This information will help define precise therapeutic targets for the prevention of pericyte injury and vascular dysfunctions. The third goal is to determine the therapeutic implication of blocking aberrant vascular inflammation in a context of dementia. This will define whether targeting vascular inflammation can indeed protect pericytes and vascular functions, and most importantly, whether fixing brain vessels can help in preserving neuronal functions and cognitive capabilities. In summary, these studies will help us understand how vascular inflammation contributes to dementia, in particular how it damages pericyte and vessel health. They will also tell us whether pericyte loss contributes to vascular inflammation which may aggravate further brain vascular leakage. Importantly, this project will also define whether therapeutically targeting brain vasculature can protect brain functions. This information will help us design treatment strategies to protect the brain in AD, and may also give insights into other diseases such as small vessel disease, where brain capillaries and pericytes are damaged early.