Pathophysiology and treatment of neurological disorders

Worldwide, neurological disorders have become the leading cause of disability, and the second leading cause of death.             The numbers of deaths and people with disabilities caused by neurological diseases have risen substantially in the past 30 years, and it is expected to increase further as a result of population growth and ageing.        The social and financial burdens imposed by these chronic, debilitating diseases include poor quality of life, high health care costs, and substantial loss of productivity. Thus, there is an urgent need to understand the disease mechanisms of these neurological disorders, and develop strategies in disease prevention and treatment for patients. This project focuses on three of the main neurological diseases: multiple sclerosis (MS), uveoretinitis and Alzheimer disease (AD).

MS is a chronic disease in which repeated episodes of inflammatory demyelization (when the body’s immune system attacks the myelin that insulates and protects the body’s nerves) result in irreversible nerve fibre injury in the central nervous system (CNS) and can substantially and adversely affect an individual’s quality of life and is associated with high costs for MS patients, their families, and society as a whole. The UK has higher MS prevalence than many other countries with around 100,000 people in this country suffering from the condition.

Posterior uveoretinitis (inflammation of the uvea layer, which can involve the retina tissue, thus also called uveoretinitis) often leads to retinal tissue damage and is a potentially blinding condition (10% of blindness in the developed countries) with a significant economic and social impact. In the UK, it is estimated that two to five in every 10,000 people will be affected by uveitis every year.

The number of individuals living with AD has more than doubled globally from 1990 to 2016 negatively affecting families, communities, and health-care systems around the world. AD is the most common form of dementia which causes progressive cognitive deterioration and is characterized by beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical grey matter, and the involvement of neuroinflammation.

Currently, there is no cure for MS, uveoretinitis or AD, and the efficacy of the available treatments is limited by many side effects. Better understanding of the underlying molecular mechanisms of these diseases will help develop better strategies to treat the patients and delay disease progression, thus helping the patients and families, as well as reducing the economic burden.

This project will use experimental autoimmune encephalomyelitis (EAE),  experimental autoimmune uveoretinitis (EAU) and 5xFAD mice, animal models of MS, uveoretinitis and AD disease respectively. EAE is an animal model of brain inflammation which is widely studied as a model of the human CNS for diseases including MS. EAE provides a valuable tool for obtaining insights into the immunobiology of MS disease and has led to the development of clinically approved therapies. For its part, EAU has contributed enormously to our understanding of uveoretinitis disease and drug development. It permits further understanding of the underlying causes and development of diseases related to the immune system of uveitis. Although EAE and EAU are separate disease models, they share similar mechanisms of immunopathogenesis (the production or development of diseases related to the immune system), the lessons we can learn from these two separate diseases will very likely benefit sufferers of either and possibly of other neurological autoimmune diseases. Our studies will also use 5xFAD mice to  improve our understanding of AD pathologies and the interaction between the CNS and the immune cells, which is the key for the development of novel therapeutic strategies for AD patients.

The project will further our understanding of the underlying immunomechanisms involved in the pathogenesis of AD, MS, uveoretinitis, and other neurological disorders, thus informing rational design of novel therapeutic strategies for patients with these diseases, all of which will have enormous impact on the economy and the health care of humans.