Prion kinetics and toxicity and their wider relevance in neurodegenerative disease

It is now recognised that the disease process central to prion diseases – seeded polymerisation of a normal brain protein (the prion protein) to form fibres known as amyloid that multiply and spread throughout the brain and damage brain cells – is of much wider relevance in commoner dementias such as Alzheimer’s disease. Much has been learned from previous work at the Unit in understanding these processes, leading to a General Model of prion propagation and neurotoxicity. An important finding is that prions are not themselves directly toxic to brain cells but rather another prion protein species is the toxic entity. We will isolate and characterise this to understand how it damages brain cells and causes disease and also develop and apply novel methods to rapidly measure prions and prion-related toxicity. Importantly, we discovered that the different types of amyloid involved in causing Alzheimer’s disease can, albeit in rare medical accidents, act as prions and cause Alzheimer’s and other disease in humans. We are finding that these other pathological protein “seeds” resemble classical prions in many ways including existing in different strains which might cause different patterns of human disease. We will identify such strains and seek to understand how they cause disease and how this can help in development of effective therapies.