Dataset Information

A?(39-42) modulates A? oligomerization but not fibril formation.

ABSTRACT: Recently, certain C-terminal fragments (CTFs) of A?42 have been shown to be effective inhibitors of A?42 toxicity. Here, we examine the interactions between the shortest CTF in the original series, A?(39-42), and full-length A?. Mass spectrometry results indicate that A?(39-42) binds directly to A? monomers and to the n = 2, 4, and 6 oligomers. The A?42:A?(39-42) complex is further probed using molecular dynamics simulations. Although the CTF was expected to bind to the hydrophobic C-terminus of A?42, the simulations show that A?(39-42) binds at several locations on A?42, including the C-terminus, other hydrophobic regions, and preferentially in the N-terminus. Ion mobility-mass spectrometry (IM-MS) and electron microscopy experiments indicate that A?(39-42) disrupts the early assembly of full-length A?. Specifically, the ion-mobility results show that A?(39-42) prevents the formation of large decamer/dodecamer A?42 species and, moreover, can remove these structures from solution. At the same time, thioflavin T fluorescence and electron microscopy results show that the CTF does not inhibit fibril formation, lending strong support to the hypothesis that oligomers and not amyloid fibrils are the A? form responsible for toxicity. The results emphasize the role of small, soluble assemblies in A?-induced toxicity and suggest that A?(39-42) inhibits A?-induced toxicity by a unique mechanism, modulating early assembly into nontoxic hetero-oligomers, without preventing fibril formation.

SUBMITTER: Gessel MM

PROVIDER: S-EPMC3271797 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Aβ(39-42) modulates Aβ oligomerization but not fibril formation.

Gessel Megan Murray MM Wu Chun C Li Huiyuan H Bitan Gal G Shea Joan-Emma JE Bowers Michael T MT

Biochemistry 20111223 1

Recently, certain C-terminal fragments (CTFs) of Aβ42 have been shown to be effective inhibitors of Aβ42 toxicity. Here, we examine the interactions between the shortest CTF in the original series, Aβ(39-42), and full-length Aβ. Mass spectrometry results indicate that Aβ(39-42) binds directly to Aβ monomers and to the n = 2, 4, and 6 oligomers. The Aβ42:Aβ(39-42) complex is further probed using molecular dynamics simulations. Although the CTF was expected to bind to the hydrophobic C-terminus of ...[more]

PMID: 22129303

Similar Datasets

Project description:Soluble amyloid oligomers are potent neurotoxins that are involved in a wide range of human degenerative diseases, including Alzheimer disease. In Alzheimer disease, amyloid beta (Abeta) oligomers bind to neuronal synapses, inhibit long term potentiation, and induce cell death. Recent evidence indicates that several immunologically distinct structural variants exist as follows: prefibrillar oligomers (PFOs), fibrillar oligomers (FOs), and annular protofibrils. Despite widespread interest, amyloid oligomers are poorly characterized in terms of structural differences and pathological significance. FOs are immunologically related to fibrils because they react with OC, a conformation-dependent, fibril-specific antibody and do not react with antibodies specific for other types of oligomers. However, fibrillar oligomers are much smaller than fibrils. FOs are soluble at 100,000 x g, rich in beta-sheet structures, but yet bind weakly to thioflavin T. EPR spectroscopy indicates that FOs display significantly more spin-spin interaction at multiple labeled sites than PFOs and are more structurally similar to fibrils. Atomic force microscopy indicates that FOs are approximately one-half to one-third the height of mature fibrils. We found that Abeta FOs do not seed the formation of thioflavin T-positive fibrils from Abeta monomers but instead seed the formation of FOs from Abeta monomers that are positive for the OC anti-fibril antibody. These results indicate that the lattice of FOs is distinct from the fibril lattice even though the polypeptide chains are organized in an immunologically identical conformation. The FOs resulting from seeded reactions have the same dimensions and morphology as the initial seeds, suggesting that the seeds replicate by growing to a limiting size and then splitting, indicating that their lattice is less stable than fibrils. We suggest that FOs may represent small pieces of single fibril protofilament and that the addition of monomers to the ends of FOs is kinetically more favorable than the assembly of the oligomers into fibrils via sheet stacking interaction. These studies provide novel structural insight into the relationship between fibrils and FOs and suggest that the increased toxicity of FOs may be due to their ability to replicate and the exposure of hydrophobic sheet surfaces that are otherwise obscured by sheet-sheet interactions between protofilaments in a fibril.

Dataset Information

A?(39-42) modulates A? oligomerization but not fibril formation.

Publications

Aβ(39-42) modulates Aβ oligomerization but not fibril formation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets