The role of prefibrillar assemblies in the pathogenesis of amyloid diseases

Abstract

The formation of amyloid fibrils is associated with a large number of major diseases including Alzheimer's disease, type 2 diabetes, prion diseases. Parkinson's disease and various famillal and systemic amyloidosis disorders. The formation of well-ordered fibrils of 7∼10 nm in diameter with a distinct X-ray fiber diffraction pattern and a β-sheet secondary structure is observed in all these amyloid diseases. The formation of the fibrils is correlated with cellular death that is co-localized with the fibrillar deposits. Nevertheless, recent studies have indicated that early prefibrillar assemblies, rather than large amyloid fibrils, may mediate the cytotoxicty that is associated with the fibrillization process. It was clearly demonstrated that unrelated amyloid-forming polypeptides form remarkably similar nanometric annular structures at the early stages of assembly. Those structures are kinetically transient and show strong membrane-interacting and -permeating abilities. The ultrastructure of the transient assemblies and their membrane activity are consistent with a membrane pore formation mechanism of cytotoxicity. The identification of prefibrillar structures as the key cytotoxic agents in amyloid disease suggests that therapeutic approaches to the treatment of amyloid diseases should be ases directed toward the early stages of molecular recognition that facilitate the formation of the early assemblies.