Manipulating the amyloid-beta aggregation pathway with chemical chaperones

Amyloid-beta (A beta) assembly into fibrillar structures is a defining char acteristic of Alzheimer's disease that is initiated by a conformational tra nsition from random coil to beta-sheet and a nucleation-dependent aggregati on process. We have investigated the role of organic osmolytes as chemical chaperones in the amyloid pathway using glycerol to mimic the effects of na turally occurring molecules, Osmolytes such as the naturally occurring trim ethylamine N-oxide and glycerol correct folding defects by preferentially h ydrating partially denatured proteins and entropically stabilize native con formations and polymeric states. Trimethylamine N-oxide and glycerol were f ound to rapidly accelerate the A beta random coil-to-beta-sheet conformatio nal change necessary for fiber formation. This was accompanied by an immedi ate conversion of amorphous unstructured aggregates into uniform globular a nd possibly nucleating structures. Osmolyte-facilitated changes in A beta h ydration also affected the final stages of amyloid formation and mediated t ransition from the protofibrils to mature fibers that are observed in vivo, These findings suggest that hydration forces can be used to control fibril assembly and may have implications for the accumulation of A beta within i ntracellular compartments such as the endoplasmic reticulum and in, vitro m odeling of the amyloid pathway.