Ageing, amyloid and amyloidosis: from pathogenesis to therapy





M.B. Pepys

Centre for Amyloidosis & Acute Phase Proteins, Department of Medicine, Royal Free & University College Medical School, University College London, Rowland Hill Street, London NW3 2PF, UK



Amyloidosis is a clinical disorder caused by extracellular deposition of insoluble abnormal fibrils, with a pathognomonic structure, derived from aggregation of misfolded, normally soluble, protein. About twenty three different unrelated proteins are known to form amyloid fibrils in vivo, each associated with clinically distinct conditions. Systemic amyloidosis, with amyloid deposits in the viscera, blood vessel walls and connective tissue, is usually fatal and is the cause of about one per thousand deaths in developed countries. In contrast to this rarity, microscopic focal amyloid deposits, localised to particular tissues, are present with increasing frequency in ageing individuals and are universal after about 80 years. The clinical significance of these deposits is not known, nor whether they contribute to normal ageing rather than specific disease.

Localised microscopic amyloid deposits are also characteristically present in other conditions, including Alzheimers disease and type 2 diabetes, but probably are not the cause of disease in contrast to the clearly evident pathogenetic role of the deposits in systemic amyloidosis. There are many other diseases, caused by and/or associated with protein misfolding, in which aggregated proteins accumulate, for example Huntingdons and related diseases, Parkinsons disease and the serpinopathies. Some of these aggregates share biophysical similarities with amyloid fibrils, leading to confusion among workers unfamiliar with pathobiology who unfortunately conflate them with amyloid. However these other conditions do not involve amyloid deposition and are not forms of amyloidosis. Furthermore, in sharp contrast to amyloidosis, there is evidence that at least some of these other forms of protein aggregation are not only not pathogenetic but are actually protective against tissue damaging pathology.

There has been much recent progress in elucidation of the natural history and response to treatment of amyloidosis, and of the molecular mechanisms of amyloid fibrillogenesis: the underlying protein misfolding and aggregation processes, and the roles of accessory molecules, especially proteoglycans and serum amyloid P component (SAP), that are universally associated with amyloid deposition in vivo. Better understanding is leading to much improved diagnosis and more effective treatments aimed at reducing the abundance of amyloid fibril precursor proteins. Novel small molecule drugs and other approaches are also beginning to emerge, targeting specific components of the fibrillogenesis pathway and accessory interactions that may be crucial for pathogenesis. Once their efficacy in clinical amyloidosis is demonstrated, exploration of the potential effects of these new treatments on normal ageing will be of interest.




Key words: Amyloid, Amyloidosis, Protein misfolding, Aggregation, Therapy







Problems or questions regarding this site should be directed to the organiser