期刊
MATHEMATICAL BIOSCIENCES
卷 273, 期 -, 页码 70-79出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.mbs.2015.12.004
关键词
Amyloid-beta; Aggregation; Oligomers; Simulation; Nucleation; Stability analysis
资金
- National Center for Research Resources [5P20RR016476-11]
- National Institute of General Medical Sciences from the National Institutes of Health through INBRE [8P20 GM103476-11]
- National Science Foundation [NSF 1351786]
- Direct For Computer & Info Scie & Enginr
- Division of Computing and Communication Foundations [1351786] Funding Source: National Science Foundation
Aggregates of amyloid-beta (A beta) peptide are known to be the key pathological agents in Alzheimer disease (AD). A beta aggregates to form large, insoluble fibrils that deposit as senile plaques in AD brains. The process of aggregation is nucleation-dependent in which the formation of a nucleus is the rate-limiting step, and controls the physiochemical fate of the aggregates formed. Therefore, understanding the properties of nucleus and pre-nucleation events will be significant in reducing the existing knowledge-gap in AD pathogenesis. In this report, we have determined the plausible range of critical nucleation number (n*), the number of monomers associated within the nucleus for a homogenous aggregation model with single unique nucleation event, by two independent methods: A reduced-order stability analysis and ordinary differential equation based numerical analysis, supported by experimental biophysics. The results establish that the most likely range of n* is between 7 and 14 and within, this range, n* = 12 closely supports the experimental data. These numbers are in agreement with those previously reported, and importantly, the report establishes a new modeling framework using two independent approaches towards a convergent solution in modeling complex aggregation reactions. Our model also suggests that the formation of large protofibrils is dependent on the nature of n*, further supporting the idea that pre-nucleation events are significant in controlling the fate of larger aggregates formed. This report has re-opened an old problem with a new perspective and holds promise towards revealing the molecular events in amyloid pathologies in the future. (C) 2015 Elsevier Inc. All rights reserved.
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