The formation of amyloid plaques starts with soluble amyloid-β monomers, which coalesce to form small oligomers, protofibrils, fibrils, and finally the amyloid plaques that pack the intraneural spaces in the brains of Alzheimer's patients. Understanding the dynamics of this process may ultimately provide the means of controlling it.

In the 23 December online version of the Journal of the Biological Chemistry, researchers in Mary Jo LaDu's lab at the Evanston Northwestern Healthcare Institute, together with colleagues at Northwestern University, Chicago, provide some new insights into this process. Using the atomic force microscope (AFM), which has a miniature stylus that traces over complex three-dimensional structures to reveal their shape much like a finger deciphering Braille, first author Blaine Stine et al. show how temperature, pH, and other environmental parameters affect the complex relationships among the different forms of Aβ. The authors found, for example, that oligomerization can occur at much lower concentrations than fibrillization, which is itself dramatically accelerated by low ionic strength or pH. Stine et al. found that dissolving dried stocks of Aβ in the acid hexafluoroisopropanol denatures aggregated peptide forms within 24 hours, leaving freely soluble Aβ monomers. This allows controlled aggregation studies to be carried out. Previously, Aβ solutions have contained small quantities of oligomers or fibrils that act as nucleation sites for macromolecular growth. These "hot spots" can skew the dynamic equilibrium between different forms of Aβ and therefore compromise the data. For example, the AFM revealed the formation of a range of aggregates and fibrils when commercially available Aβ1-42 was dissolved in deionized water or even anhydrous DMSO, as recommended by some protocols. This is important because it reinforces again that the Aβ widely used in various cell-culture assays is a heterogeneous mixture.—Tom Fagan

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Primary Papers

  1. . In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis. J Biol Chem. 2003 Mar 28;278(13):11612-22. PubMed.