Global fitting and parameter identifiability for amyloid-β aggregation with competing pathways

Rana, Pratip; Bose, Priyankar; Vaidya, Ashwin; Rangachari, Vijay; Ghosh, Preetam

doi:10.1109/bibe50027.2020.00020

Cited by 2 publications

(6 citation statements)

References 22 publications

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“…Our Aβ competing pathways model using the ensemble kinetic simulation-based method also needs a gradient-free parameter optimization algorithm as it consists of several biochemical reactions from the competing pathways that makes the gradient-based models less effective. In fact, we reported the performance of different optimization methods for the competing pathways simulation in ref and validated that derivative-free methods work best in this context.…”

Section: Experimental Proceduresmentioning

confidence: 67%

“…Optimization methods can be gradient-independent or gradient-based; the former method is theoretically less susceptible to stochastic noise than the latter method. Hence, in this case of stochastic optimization, we have used gradient-free metaheuristics , as our algorithm for parameter estimation. The following modeling abstraction was used in this study.…”

Section: Experimental Proceduresmentioning

confidence: 99%

“…As a result, metaheuristics are more computationally expensive and might fail in some cases. Various types of metaheuristics are differential evolution, simulated annealing, genetic algorithms, harmony search, bee algorithms, and so on. ,− …”

Section: Experimental Proceduresmentioning

confidence: 99%

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Ganglioside-Enriched Phospholipid Vesicles Induce Cooperative Aβ Oligomerization and Membrane Disruption

et al. 2022

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A major hallmark of Alzheimer's disease (AD) is the accumulation of extracellular aggregates of amyloid-β (Aβ). Structural polymorphism observed among Aβ fibrils in AD brains seem to correlate with the clinical subtypes suggesting a link between fibril polymorphism and pathology. Since fibrils emerge from a templated growth of low-molecular-weight oligomers, understanding the factors affecting oligomer generation is important. Membrane lipids are key factors to influence early stages of Aβ aggregation and oligomer generation, which cause membrane disruption. We have previously demonstrated that conformationally discrete Aβ oligomers can be generated by modulating the charge, composition, and chain length of lipids and surfactants. Here, we extend our studies into liposomal models by investigating Aβ oligomerization on large unilamellar vesicles (LUVs) of total brain extracts (TBE), reconstituted lipid rafts (LRs), or 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). Varying the vesicle composition by specifically increasing the amount of GM1 gangliosides as a constituent, we found that only GM1-enriched liposomes induce the formation of toxic, low-molecular-weight oligomers. Furthermore, we found that the aggregation on liposome surface and membrane disruption are highly cooperative and sensitive to membrane surface characteristics. Numerical simulations confirm such a cooperativity and reveal that GM1-enriched liposomes form twice as many pores as those formed in the absence GM1. Overall, this study uncovers mechanisms of cooperativity between oligomerization and membrane disruption under controlled lipid compositional bias, and refocuses the significance of the early stages of Aβ aggregation in polymorphism, propagation, and toxicity in AD.

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Section: Experimental Proceduresmentioning

confidence: 67%

Section: Experimental Proceduresmentioning

confidence: 99%

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Ganglioside-Enriched Phospholipid Vesicles Induce Cooperative Aβ Oligomerization and Membrane Disruption

et al. 2022

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“…We used Scatter Search optimization algorithm to fit the experimental data as it has been earlier shown that metaheuristic algorithms like scatter performs better than other algorithms to fit the Aβ aggregation 45 . Sum of squared errors (SSE) was used as a metric to evaluate the models, and COmplex PAthway SImulator (COPASI) 46 to solve the mathematical models. Briefly, oligomerization was considered up to the formation of 12mers, beyond which all aggregates were considered ‘fibrils’ for modeling simplicity.…”

Section: Resultsmentioning

confidence: 99%

“…Optimization methods can be gradient-independent or gradient-based; the former method is theoretically less susceptible to the stochastic noise than the latter method. Hence, in this case of stochastic optimization, we have used gradient-free metaheuristics 45,46 as our algorithm for parameter estimation. The following modelling abstraction was used in this study.…”

Section: Model Simulationsmentioning

confidence: 99%

Ganglioside enriched phospholipid vesicles induce cooperative Aβ oligomerization and membrane disruption

Saha

Bose

Dhakal

et al. 2022

Preprint

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A major hallmark of Alzheimer disease (AD) is the accumulation of extracellular aggregates of amyloid-β (Aβ). Structural polymorphism observed among Aβ fibrils in AD brains seem to correlate with the clinical sub-types suggesting a link between fibril polymorphism and pathology. Since fibrils emerge from a templated growth of low-molecular weight oligomers, understanding the factors affecting oligomer generation is important. The membrane lipids are key factors that influence early stages of Aβ aggregation and oligomer generation, and cause membrane disruption. We have previously showed that conformationally discrete Aβ oligomers can be generated by modulating the charge, composition, chain length of lipids and surfactants. Here, we extend our studies into liposomal models by investigating Aβ oligomerization on large unilamellar vesicles (LUVs) of total brain extracts (TBE), reconstituted lipid rafts (LRs) or 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). Specifically, we varied the vesicle composition by varying the amount of GM1 gangliosides added as a constituent. We found that liposomes enriched in GM1 induce the formation of toxic, low-molecular weight oligomers that are isolable in a lipid-complexed form. Importantly, the data indicate that the oligomer formation and membrane disruption are highly cooperative processes. Numerical simulations on the experimental data confirm cooperativity and reveal that GM1-enriched liposomes form twice as many numbers of pores as those without GM1. Overall, this study uncovers mechanisms of cooperativity between oligomerization and membrane disruption under specific lipid compositional bias, and refocuses the significance of the early stages of Aβ aggregation in polymorphism, propagation, and toxicity in AD.

show abstract

Global fitting and parameter identifiability for amyloid-β aggregation with competing pathways

Cited by 2 publications

References 22 publications

Ganglioside-Enriched Phospholipid Vesicles Induce Cooperative Aβ Oligomerization and Membrane Disruption

Ganglioside-Enriched Phospholipid Vesicles Induce Cooperative Aβ Oligomerization and Membrane Disruption

Ganglioside enriched phospholipid vesicles induce cooperative Aβ oligomerization and membrane disruption

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