18 December 2002. In Alzheimer's brains there exists a complex, dynamic equilibrium among the various soluble and fibrillar forms of the Aβ protein (for a recent review, see Kirkitadze et al., 2002). In this week's PNAS early online edition, researchers from Brigham and Women's Hospital in Boston, and MIT in Cambridge, Massachusetts, unveil some of the intermediaries that lead to the formation of amyloid fibrils. Their work may explain, in part, why Aβ42 is more amyloidogenic than Aβ40.
First author Gal Bitan and colleagues, working with David Teplow, used a technique known as PICUP (photo-induced cross-linking of unmodified proteins) to rapidly and covalently link Aβ monomers as they formed larger multimeric structures. Bitan et al. then denatured and separated the mixture to identify what oligomers were formed. The authors found that, while Aβ40 predominantly formed dimers, trimers, and tetramers, Aβ42 formed pentamers and hexamers, with the latter combining to form dodecamer and hexadecamer units.
Bitan et al. also used light-scattering spectroscopy to identify, in solution, larger but less abundant particles of Aβ. Here, again, differences were observed, with Aβ40 forming both large (~100 nm diameter) and small (~1-2 nm diameter) particles, while Aβ42 formed large and medium-sized (10-25 nm diameter) particles. Furthermore, when viewed using the electron microscope, Aβ40 particles were seen to be mostly amorphous, whereas Aβ42 particles had a "bead-on-a-string" structure.
The data indicate that the dynamics of particle formation are quite different for the two Aβ isoforms. In support of this idea, the authors found that extension of the smaller isoform by one amino acid (isoleucine) was sufficient to allow formation of pentamers and hexamers, but not the larger multimers, formation of which seems to depend on the presence of the alanine 42.-Tom Fagan.
Bitan G, Kirkitadze MD, Lomakin A, Vollers SS, Benedek GB, Teplow DB. Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways. PNAS early online edition 2002 December 2. Abstract
Kirkitadze MD, Bitan G, and Teplow DB. Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies. J. Neurosci. Res. 2002;69:567-577. Abstract.