Identification and characterization of key kinetic intermediates in amyloid beta-protein fibrillogenesis.

By M. Kirkitadze, M. Condron, David B. Teplow. Journal of Molecular Biology, 2001

651 citations recorded by the source corpus.

Amyloid beta-protein (Abeta) assembly into toxic oligomeric and fibrillar structures is a seminal event in Alzheimer's disease, therefore blocking this process could have significant therapeutic benefit. A rigorous mechanistic understanding of Abeta assembly would facilitate the targeting and design of fibrillogenesis inhibitors. Prior studies have shown that Abeta fibrillogenesis involves conformational changes leading to the formation of extended beta-sheets and that an alpha-helix-containing intermediate may be involved. However, the significance of this intermediate has been a matter of debate. We report here that the formation of an oligomeric, alpha-helix-containing assembly is a key step in Abeta fibrillogenesis. The generality of this phenomenon was supported by conformational studies of 18 different Abeta peptides, including wild-type Abeta(1-40) and Abeta(1-42), biologically relevant truncated and chemically modified Abeta peptides, and Abeta peptides causing familial forms of cerebral amyloid angiopathy. Without exception, fibrillogenesis of these peptides involved an oligomeric alpha-helix-containing intermediate and the kinetics of formation of the intermediate and of fibrils was temporally correlated. The kinetics varied depending on amino acid sequence and the extent of peptide N- and C-terminal truncation. The pH dependence of helix formation suggested that Asp and His exerted significant control over this process and over fibrillogenesis in general. Consistent with this idea, Abeta peptides containing Asp-->Asn or His-->Gln substitutions showed altered fibrillogenesis kinetics. These data emphasize the importance of the dynamic interplay between Abeta monomer conformation and oligomerization state in controlling fibrillogenesis kinetics.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/599af01a0d652e17dd84d169f9bd47eaa846bf31

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

In Physiology

Citations in the corpus

Conformational constraints for amyloid fibrillation: the importance of being unfolded. (2004, background): “NMR studies have shown that monomers of Ah(1–40) or Ah(1–42) possess no ahelical or h-sheet structure [160], i.”
The role of microglia in amyloid clearance from the AD brain (2010, background): “Because of the two extra C-terminal amino acid residues, Ab42 is more hydrophobic than Ab40 and has a greater propensity to polymerize and form fibrils (Kirkitadze et al. 2001; Walsh et al. 1997).”
Solution structure of the Alzheimer amyloid beta-peptide (1-42) in an apolar microenvironment. Similarity with a virus fusion domain. (2002, background): “Thus, for example, it has been recently reported that the fibrillogenesis process of Ab-(1–40) and Ab-(1–42) involves an oligomeric a-helical intermediate [11].”
Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: The emerging role of oligomeric assemblies (2002, positive): “The oligomerization and helix 3 sheet conversion events which occur during prion assembly have also been postulated to mediate A (cid:1) assembly (Walsh et al., 1999; Kirkitadze et al., 2001).”
Intrinsically disordered proteins in human diseases: introducing the D2 concept. (2008, background): “Partial refolding to the premolten globule-like conformation has been detected at the earliest stages of Aβ fibrillation (80).”