Physical, morphological and functional differences between ph 5.8 and 7.4 aggregates of the Alzheimer's amyloid peptide Abeta.
The Alzheimer's amyloid peptide Abeta(1-40) generates a turbid, Congo re-binding aggregation reaction product within minutes when incubated in the pH range 5 to 6. At pH 7.4, Abeta forms little or no aggregate in this time frame, requiring hours or days, rather than minutes, to complete fibril formation. The pH 5.8 aggregates are not amyloid fibrils, but rather appear in electron micrographs as a mixture of larger particles of different morphologies. These aggregates differ from classical fibrils by a number of other measures. Per mass of peptide aggregated, the pH 5.8 product binds less Congo red and thioflavin T than does aggregate grow in unstirred reactions at pH 7.4. Both the pH 5.8 and 7.4 aggregates exhibit light scattering at 90 degrees. However, while the pH 5.8 aggregate is visible in suspension by the light microscopy, and exhibits turbidity at 405 nm, the fibrils grown at pH 7.4 in an unstirred reaction are transparent. The two aggregate types do not interconvert in pH shift experiments. Most dramatically, and in contrast to 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 processing of betaAPP to generate Abeta 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.
Wood
S J
SJ
Department of Macromolecular Sciences and Toxicology, SmithKline Beecham Pharmaceutials, King of Prussia, PA 19406, USA.
Maleeff
B
B
Hart
T
T
Wetzel
R
R
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008027:Light; D046911:Macromolecular Substances; D008854:Microscopy, Electron; D009391:Nephelometry and Turbidimetry; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000648:ultrastructure; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D012542:Scattering, Radiation
D000682:Amyloid; D016229:Amyloid beta-Peptides; D046911:Macromolecular Substances; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)