Fig. 2. Schematic of amyloid formation.

Native proteins are in dynamic equilibrium with their less-structured, partially folded and/or unfolded states. One (or possibly several) of these states initiates amyloid fibril formation by assembling into oligomeric species. The precursor of aggregation (native, partially folded or unfolded) may differ for different protein sequences. Oligomeric species can then assemble further to form higher-order oligomers, one or more of which can form a fibril nucleus, which, by rapidly recruiting other monomers, can nucleate assembly into amyloid fibrils. This process occurs in the lag time (nucleation phase) of assembly. As fibrils grow, they can fragment, yielding more fibril ends that are capable of elongation by the addition of new aggregation-prone species^140,144,145. This elongation results in an exponential growth of fibrillar material (blue line) until nearly all free monomer is converted into a fibrillar form. Fibrils are dynamic and can release oligomers that may or may not be toxic¹⁷⁷. Fibrils can also associate further with each other, with other proteins and with non-proteinaceous factors¹⁸⁸ (not shown here) to form the amyloid plaques and intracellular inclusions characteristic of amyloid disease. Note that any and/or all of these steps are potential points for drug intervention.