Dataset Information

Inhibition of amyloid beta fibril formation by monomeric human transthyretin.

ABSTRACT: Transthyretin (TTR) is a homotetrameric protein that is found in the plasma and cerebrospinal fluid. Dissociation of TTR tetramers sets off a downhill cascade of amyloid formation through polymerization of monomeric TTR. Interestingly, TTR has an additional, biologically relevant activity, which pertains to its ability to slow the progression of amyloid beta (A?) associated pathology in transgenic mice. In vitro, both TTR and a kinetically stable variant of monomeric TTR (M-TTR) inhibit the fibril formation of A?1-40/42 molecules. Published evidence suggests that tetrameric TTR binds preferentially to A? monomers, thus destabilizing fibril formation by depleting the pool of A? monomers from aggregating mixtures. Here, we investigate the effects of M-TTR on the in vitro aggregation of A?1-42 . Our data confirm previous observations that fibril formation of A? is suppressed in the presence of sub-stoichiometric amounts of M-TTR. Despite this, we find that sub-stoichiometric levels of M-TTR are not bona fide inhibitors of aggregation. Instead, they co-aggregate with A? to promote the formation of large, micron-scale insoluble, non-fibrillar amorphous deposits. Based on fluorescence correlation spectroscopy measurements, we find that M-TTR does not interact with monomeric A?. Two-color coincidence analysis of the fluorescence bursts of A? and M-TTR labeled with different fluorophores shows that M-TTR co-assembles with soluble A? aggregates and this appears to drive the co-aggregation into amorphous precipitates. Our results suggest that mimicking the co-aggregation activity with protein-based therapeutics might be a worthwhile strategy for rerouting amyloid beta peptides into inert, insoluble, and amorphous deposits.

SUBMITTER: Garai K

PROVIDER: S-EPMC6032350 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inhibition of amyloid beta fibril formation by monomeric human transthyretin.

Garai Kanchan K Posey Ammon E AE Li Xinyi X Buxbaum Joel N JN Pappu Rohit V RV

Protein science : a publication of the Protein Society 20180314 7

Transthyretin (TTR) is a homotetrameric protein that is found in the plasma and cerebrospinal fluid. Dissociation of TTR tetramers sets off a downhill cascade of amyloid formation through polymerization of monomeric TTR. Interestingly, TTR has an additional, biologically relevant activity, which pertains to its ability to slow the progression of amyloid beta (Aβ) associated pathology in transgenic mice. In vitro, both TTR and a kinetically stable variant of monomeric TTR (M-TTR) inhibit the fibr ...[more]

PMID: 29498118

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

Inhibition of amyloid beta fibril formation by monomeric human transthyretin.

Publications

Inhibition of amyloid beta fibril formation by monomeric human transthyretin.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets