PHYSICAL, MORPHOLOGICAL AND FUNCTIONAL DIFFERENCES BETWEEN PH 5.8 AND7.4 AGGREGATES OF THE ALZHEIMERS AMYLOID PEPTIDE AP

The Alzheimer's amyloid peptide A beta(1-40) generates a turbid, Congo red-binding aggregation reaction product within minutes when incubate d in the pH range 5 to 6. At pH 7.4, A beta forms little or no aggrega te in this time frame, requiring hours or days, rather than minutes, t o complete fibril formation. The pH 5.8 aggregates are not amyloid fib rils but rather appear in electron micrographs as a mixture of larger particles of different morphologies. These aggregates differ from clas sical fibrils by a number of other measures. Per mass of peptide aggre gated, the pH 5.8 product binds less Congo red and thioflavin T than d oes aggregate grown in unstirred reactions at pH 7.4. Both the pH 5.8 and 7.4 aggregates exhibit light scattering at 90 degrees. However, wh ile the pH 5.8 aggregate is visible in suspension by light microscopy, and exhibits turbidity at 405 nm, the fibrils grown at pH 7.4 in an u nstirred reaction are transparent. The two aggregate types do not inte rconvert in pH shift experiments. Most dramatically, and in contrast t o fibrils grown at pH 7.4, the turbid aggregate generated at pH 5.8 is incapable of seeding fibril growth at pH 7.4. Although proteolytic pr ocessing of beta APP to generate A beta probably takes place in a low pH compartment of the cell, our results suggest that fibril formation is not likely to be initiated in such an environment. (C) 1996 Academi c Press Limited