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Estimating the dynamics of protofibril elongation involved in Aβ42 peptide aggregation in Alzheimer's disease

Published: 02 August 2010 Publication History

Abstract

We present a molecular-level simulation model to understand the dynamics of the amyloid-β (Aβ) peptide aggregation process involved in Alzheimer's disease (AD). We propose a divide and conquer strategy by dissecting the aggregation pathway into three stages: 1) pre-nucleation 2) post-nucleation and 3) protofibril elongation. We next focus on estimating the rate constants involved in the protofibril elongation stage for Aβ42 supported by in vitro biophysical analyses data. These rate constants will allow us to build a complete simulation of the aggregation pathway.

References

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Harper, JD and Lansbury, PT, (1997) Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins, Annu Rev Biochem 66, 385--407.
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Walsh, DM, Lomakin, A, Benedek, GB, Condron, MM, and Teplow, DB (1997) Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate, J Biol Chem 272, 22364--22372.
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Nichols, MR, Moss, MA, Reed, DK, Lin, WL, Mukhopadhyay, R, Hoh, JH, Rosenberry, TL (2002) Growth of beta-amyloid(1--40) protofibrils by monomer elongation and lateral association. Characterization of distinct products by light scattering and atomic force microscopy, Biochemistry 41, 6115--6127.
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Blackley, HK, Sanders, GH, Davies, MC, Roberts, CJ, Tendler, SJ, and Wilkinson, MJ (2000) In-situ atomic force microscopy study of beta-amyloid fibrillization, J Mol Biol 298, 833--840.
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Lee, CC, Nayak, A, Sethuraman, A, Belfort, G, and McRae, GJ (2007) A three-stage kinetic model of amyloid fibrillation, Biophys J 92, 3448--3458.
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  • (2012)Specific Soluble Oligomers of Amyloid-β Peptide Undergo Replication and Form Non-fibrillar Aggregates in Interfacial EnvironmentsJournal of Biological Chemistry10.1074/jbc.M112.355156287:25(21253-21264)Online publication date: 27-Apr-2012

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cover image ACM Conferences
BCB '10: Proceedings of the First ACM International Conference on Bioinformatics and Computational Biology
August 2010
705 pages
ISBN:9781450304382
DOI:10.1145/1854776
Permission to make digital or hard copies of all or part of this work for personal or classroom use is granted without fee provided that copies are not made or distributed for profit or commercial advantage and that copies bear this notice and the full citation on the first page. Copyrights for components of this work owned by others than ACM must be honored. Abstracting with credit is permitted. To copy otherwise, or republish, to post on servers or to redistribute to lists, requires prior specific permission and/or a fee. Request permissions from [email protected]

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Association for Computing Machinery

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Published: 02 August 2010

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Author Tags

  1. chemical reaction kinetics
  2. ordinary differential equations

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Overall Acceptance Rate 254 of 885 submissions, 29%

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View all
  • (2012)Specific Soluble Oligomers of Amyloid-β Peptide Undergo Replication and Form Non-fibrillar Aggregates in Interfacial EnvironmentsJournal of Biological Chemistry10.1074/jbc.M112.355156287:25(21253-21264)Online publication date: 27-Apr-2012

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