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In transthyretin (TTR)-related amyloidosis, wild-type TTR (WT-TTR), as well as mutated TTRs play important roles in the pathogenesis of senile systemic amyloidosis and familial amyloidotic polyneuropathy. However, WT-TTR usually forms stable tetramers at physiological pH, and the mechanism of such fibril formation under physiological conditions remains to be elucidated. In this study, we demonstrated WT-TTR amyloid fibril formation at physiological pH with ultrasonication. Cross-linked SDS-PAGE and circular dichroism revealed that ultrasonication induced both tetrameric TTR dissociation and monomeric TTR denaturation. These results indicate that extremely low pH is not an essential condition for TTR amyloid fibril formation if TTR is degenerated in such conditions. In addition, this method allows analysis of accelerator factors or inhibitory agents in TTR amyloid fibril formation at neutral pH.

The VIII International Symposium on Amyloidosis was held in Rochester, Minnesota, August 7 through 11, 1998. The program consisted of six sessions, each of which was devoted to a specific area of amyloidosis research. Attendance approached 250, representing 13 countries. The session on Saturday morning opened with a talk (A. Cohen, Boston) stressing the scientific importance of and the widespread acceptance of the Society's journal AMYLOID. despite its limited subscription rate. The session was then devoted to fibril formation, P component and common elements. Dr. J. Kelly (La Jolla, California) gave an excellent address on the factors responsible for the formation of fibrils from an intermediate prefibril. He emphasized studies that demonstrated that flufenamic acid and possibly fenoprofen could be potential inhibitors of fibrillogenesis in transthyretin amyloidosis. Dr. M. Pepys (London) gave an important overview of amyloid P component and its universal association with the amyloid fibril. He noted tha...

Amyloid deposits are associated with a variety of amyloid diseases, although their role in the pathogenesis remains unclear. Detection of amyloid fibrils and/or prevention of their formation appears to be important in the diagnosis and treatment of amyloid diseases such as Alzheimer's disease. The design of therapeutic molecules with this activity requires a detailed understanding of the structure of the amyloid fibril and the mechanism of fibril formation. This review is focused on studies carried out in the laboratories of the authors, who were trained as organic chemists and bring that perspective to their work. The ongoing studies described within have as their ultimate goal the complete description of the molecular mechanism of amyloid formation by two proteins; transthyretin and the amyloid protein. The purpose of this review is to outline chemical approaches and methodology which prove to be useful for understanding amyloid fibril formation.

here is a large amount of support in the literature for the concept that amyloid fibril precursor proteins unT dergo changes in the conformation leading to amyloidogenic proteins that self-assemble and turn into fibrils. Since the relationship between the pathological and non-pathological proteins would be expected to be encoded within the primary structure, elucidation ofthe primary structure is an important factor for the understanding of the fibril formation. We report here the primary structure of a glycosylated protein AL of lambda I type.