The expanded prion paradigm and amyloid-beta diseases

Prions are infectious proteins which cause fatal brain diseases in humans and other mammals, the most well-known of which is Creutzfeldt-Jakob Disease (CJD). Prions have unusual biological properties, including the ability to reproduce themselves (self-propagate) without the need for DNA or similar molecules. These behaviours were always considered unique to a single protein called the prion protein, but recent events have challenged these assumptions. The amyloid-beta protein causes two human diseases: Alzheimer’s disease, a dementia that causes memory and thinking difficulties; and cerebral amyloid angiopathy (CAA), which causes haemorrhagic (bleeding) strokes. In the last decade, doctors have identified patients who have developed Alzheimer’s disease and CAA at an unusually young age. All these patients had medical procedures many years earlier, often in childhood, and most procedures involved “cadaveric” (i.e. provided by people after death) material. These young patients developed Alzheimer’s disease or CAA because abnormal amyloid-beta protein was transferred to them via this cadaveric material, resulting in disease decades later. The very same medical procedures are known to have caused iatrogenic (medically acquired) CJD after transfer of abnormal prion protein by this route. The existence of these iatrogenic forms of Alzheimer’s disease and CAA, together with three decades of animal model data, strongly suggests that amyloid-beta can sometimes act as a prion. Although these iatrogenic forms are likely to be rare, the disease mechanisms causing them might be important for “sporadic” (without apparent cause) forms of these conditions, which are much more common, particularly at older ages. If this is the case, prion biology provides a unique framework for understanding how and why amyloid-beta causes disease, and could help identify new strategies for prevention and treatment. The programme of research described in this Fellowship has two aims. The first is to better understand iatrogenic forms of Alzheimer’s disease and CAA by working with patients with these conditions, as well as people at risk of developing them (i.e. those with known exposure to cadaveric material, specifically cadaveric human growth hormone). The second aim is to expand the prion experimental toolkit for amyloid-beta, with the eventual goal of developing a range of biological assays equivalent to that for the prion protein. This experimental toolkit would have several applications and could be used to test mechanistic hypotheses, including whether Alzheimer’s disease and CAA can be caused by different versions (strains) of amyloid-beta. It could also be used to build biological plausibility and address important outstanding public health questions about other procedures which might transmit amyloid-beta. This is particularly relevant to the question of whether amyloid-beta diseases can be transmitted by blood transfusions, as there are data from a large Scandinavian study (over 1 million participants) that suggest this might be possible. The MRC Prion Unit at UCL recently hosted a workshop attended by a range of stakeholders, including senior representatives from the Department of Health and Social Care, UK Health Security Agency and NHS Blood and Transplant, to discuss this possibility; our discussions highlighted the need to develop robust experimental methods to explore this question. The projects in this fellowship will take the next steps in developing this experimental toolkit for amyloid-beta, and will apply new biological assays to explore the questions of amyloid-beta strains and blood-borne amyloid-beta transmission.