Determination of critical nucleation number for a single nucleation amyloid-β aggregation model

Preetam Ghosh, Ashwin Vaidya, Amit Kumar, Vijayaraghavan Rangachari

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Aggregates of amyloid-β (Aβ) peptide are known to be the key pathological agents in Alzheimer disease (AD). Aβ 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.

Original languageEnglish
Pages (from-to)70-79
Number of pages10
JournalMathematical Biosciences
Volume273
DOIs
StatePublished - 1 Mar 2016

Fingerprint

protein aggregates
amyloid
Nucleation
Amyloid
Aggregation
Alzheimer Disease
Alzheimer disease
Agglomeration
Alzheimer's Disease
Nucleus
Biophysics
Amyloid Plaques
biophysics
Range of data
Model
Dependent
Pathology
Convergence of numerical methods
Peptides
Modeling

Keywords

  • Aggregation
  • Amyloid-β
  • Nucleation
  • Oligomers
  • Simulation
  • Stability analysis

Cite this

Ghosh, Preetam ; Vaidya, Ashwin ; Kumar, Amit ; Rangachari, Vijayaraghavan. / Determination of critical nucleation number for a single nucleation amyloid-β aggregation model. In: Mathematical Biosciences. 2016 ; Vol. 273. pp. 70-79.
@article{fccc6550554d482b856550696665faf8,
title = "Determination of critical nucleation number for a single nucleation amyloid-β aggregation model",
abstract = "Aggregates of amyloid-β (Aβ) peptide are known to be the key pathological agents in Alzheimer disease (AD). Aβ 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.",
keywords = "Aggregation, Amyloid-β, Nucleation, Oligomers, Simulation, Stability analysis",
author = "Preetam Ghosh and Ashwin Vaidya and Amit Kumar and Vijayaraghavan Rangachari",
year = "2016",
month = "3",
day = "1",
doi = "10.1016/j.mbs.2015.12.004",
language = "English",
volume = "273",
pages = "70--79",
journal = "Mathematical Biosciences",
issn = "0025-5564",
publisher = "Elsevier Inc.",

}

Determination of critical nucleation number for a single nucleation amyloid-β aggregation model. / Ghosh, Preetam; Vaidya, Ashwin; Kumar, Amit; Rangachari, Vijayaraghavan.

In: Mathematical Biosciences, Vol. 273, 01.03.2016, p. 70-79.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Determination of critical nucleation number for a single nucleation amyloid-β aggregation model

AU - Ghosh, Preetam

AU - Vaidya, Ashwin

AU - Kumar, Amit

AU - Rangachari, Vijayaraghavan

PY - 2016/3/1

Y1 - 2016/3/1

N2 - Aggregates of amyloid-β (Aβ) peptide are known to be the key pathological agents in Alzheimer disease (AD). Aβ 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.

AB - Aggregates of amyloid-β (Aβ) peptide are known to be the key pathological agents in Alzheimer disease (AD). Aβ 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.

KW - Aggregation

KW - Amyloid-β

KW - Nucleation

KW - Oligomers

KW - Simulation

KW - Stability analysis

UR - http://www.scopus.com/inward/record.url?scp=84960470735&partnerID=8YFLogxK

U2 - 10.1016/j.mbs.2015.12.004

DO - 10.1016/j.mbs.2015.12.004

M3 - Article

C2 - 26774039

AN - SCOPUS:84960470735

VL - 273

SP - 70

EP - 79

JO - Mathematical Biosciences

JF - Mathematical Biosciences

SN - 0025-5564

ER -