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Purified and synthetic Alzheimer's amyloid beta (A?) prions.

ABSTRACT: The aggregation and deposition of amyloid-? (A?) peptides are believed to be central events in the pathogenesis of Alzheimer's disease (AD). Inoculation of brain homogenates containing A? aggregates into susceptible transgenic mice accelerated A? deposition, suggesting that A? aggregates are capable of self-propagation and hence might be prions. Recently, we demonstrated that A? deposition can be monitored in live mice using bioluminescence imaging (BLI). Here, we use BLI to probe the ability of A? aggregates to self-propagate following inoculation into bigenic mice. We report compelling evidence that A? aggregates are prions by demonstrating widespread cerebral ?-amyloidosis induced by inoculation of either purified A? aggregates derived from brain or aggregates composed of synthetic A?. Although synthetic A? aggregates were sufficient to induce A? deposition in vivo, they exhibited lower specific biological activity compared with brain-derived A? aggregates. Our results create an experimental paradigm that should lead to identification of self-propagating A? conformations, which could represent novel targets for interrupting the spread of A? deposition in AD patients.

SUBMITTER: Stohr J

PROVIDER: S-EPMC3390876 | biostudies-other | 2012 Jul

REPOSITORIES: biostudies-other

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Purified and synthetic Alzheimer's amyloid beta (Aβ) prions.

Stöhr Jan J Watts Joel C JC Mensinger Zachary L ZL Oehler Abby A Grillo Sunny K SK DeArmond Stephen J SJ Prusiner Stanley B SB Giles Kurt K

Proceedings of the National Academy of Sciences of the United States of America 20120618 27

The aggregation and deposition of amyloid-β (Aβ) peptides are believed to be central events in the pathogenesis of Alzheimer's disease (AD). Inoculation of brain homogenates containing Aβ aggregates into susceptible transgenic mice accelerated Aβ deposition, suggesting that Aβ aggregates are capable of self-propagation and hence might be prions. Recently, we demonstrated that Aβ deposition can be monitored in live mice using bioluminescence imaging (BLI). Here, we use BLI to probe the ability of ...[more]

PMID: 22711819

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Project description:BackgroundMisfolding and self-assembly of Amyloid-β (Aβ) peptides into amyloid fibrils is pathologically linked to the development of Alzheimer's disease. Polymorphic Aβ structures derived from monomers to intermediate oligomers, protofilaments, and mature fibrils have been often observed in solution. Some aggregates are on-pathway species to amyloid fibrils, while the others are off-pathway species that do not evolve into amyloid fibrils. Both on-pathway and off-pathway species could be biologically relevant species. But, the lack of atomic-level structural information for these Aβ species leads to the difficulty in the understanding of their biological roles in amyloid toxicity and amyloid formation.Methods and findingsHere, we model a series of molecular structures of Aβ globulomers assembled by monomer and dimer building blocks using our peptide-packing program and explicit-solvent molecular dynamics (MD) simulations. Structural and energetic analysis shows that although Aβ globulomers could adopt different energetically favorable but structurally heterogeneous conformations in a rugged energy landscape, they are still preferentially organized by dynamic dimeric subunits with a hydrophobic core formed by the C-terminal residues independence of initial peptide packing and organization. Such structural organizations offer high structural stability by maximizing peptide-peptide association and optimizing peptide-water solvation. Moreover, curved surface, compact size, and less populated β-structure in Aβ globulomers make them difficult to convert into other high-order Aβ aggregates and fibrils with dominant β-structure, suggesting that they are likely to be off-pathway species to amyloid fibrils. These Aβ globulomers are compatible with experimental data in overall size, subunit organization, and molecular weight from AFM images and H/D amide exchange NMR.ConclusionsOur computationally modeled Aβ globulomers provide useful insights into structure, dynamics, and polymorphic nature of Aβ globulomers which are completely different from Aβ fibrils, suggesting that these globulomers are likely off-pathway species and explaining the independence of the aggregation kinetics between Aβ globulomers and fibrils.

Dataset Information

Purified and synthetic Alzheimer's amyloid beta (A?) prions.

Publications

Purified and synthetic Alzheimer's amyloid beta (Aβ) prions.

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