Determination of Critical Nucleation Number for a Single Nucleation Amyloid-beta Aggregation Model

Document Type

Article

Publication Date

3-2016

Department

Chemistry and Biochemistry

Abstract

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.

Publication Title

Mathematical Biosciences

Volume

273

First Page

70

Last Page

79

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