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

2020 ◽  
Author(s):  
Pratip Rana ◽  
Priyankar Bose ◽  
Ashwin Vaidya ◽  
Vijay Rangachari ◽  
Preetam Ghosh
Keyword(s):  
Amyloid Β ◽  
Parameter Identifiability ◽  
Global Fitting ◽  
Competing Pathways

scholarly journals A game theoretic approach to deciphering the dynamics of amyloid-β aggregation along competing pathways

2019 ◽  
Author(s):  
Preetam Ghosh ◽  
Pratip Rana ◽  
Vijayaraghavan Rangachari ◽  
Jhinuk Saha ◽  
Edward Steen ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Theoretic Model ◽  
Mathematical Framework ◽  
Theoretic Approach ◽  
Formation Pathway ◽  
Heterotypic Interactions ◽  
Game Theoretic ◽  
On And Off Pathways ◽  
And Behavior ◽  
Competing Pathways

AbstractAggregation of amyloidβ(Aβ) peptides is a significant event that underpins Alzheimer disease (AD). Aβaggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD pathogenesis. Therefore, there is increasing interest in understanding their formation and behavior. In this paper, we use our previously established investigations on heterotypic interactions between Aβand fatty acids (FAs) that adopt off-fibril formation pathway under the control ofFAconcentrations, to develop a mathematical framework in defining this complex mechanism. We bring forth the use of novel game theoretic framework based on the principles of Nash equilibria to define and simulate the competing on- and off-pathways of Aβaggregation. Together with detailed simulations and biophysical experiments, our mathematical models define the dynamics involved in the mechanisms of Aβaggregation in the presence ofFAs to adopt multiple pathways. Specifically, our game theoretic model indicates that the emergence of off- or on-pathway aggregates are tightly controlled by a narrow set of rate constant parameters, and one could alter such parameters to populate a particular oligomeric species. These models agree with the detailed simulations and experimental data on usingFAas a heterotypic partner to modulate temporal parameters. Predicting spatiotemporal landscape along competing pathways for a given heterotypic partner such as biological lipids is a first step towards simulating physiological scenarios in which the generation of specific conformeric strains of Aβcould be predicted. Such an approach could be profoundly significant in deciphering the biophysics of amyloid aggregation and oligomer generation, which is ubiquitously observed in many neurodegenerative diseases.

scholarly journals A game-theoretic approach to deciphering the dynamics of amyloid- β aggregation along competing pathways

2020 ◽  
Vol 7 (4) ◽  
pp. 191814 ◽  
Author(s):  
Preetam Ghosh ◽  
Pratip Rana ◽  
Vijayaraghavan Rangachari ◽  
Jhinuk Saha ◽  
Edward Steen ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Mathematical Framework ◽  
Theoretic Approach ◽  
Toxic Agents ◽  
Heterotypic Interactions ◽  
Game Theoretic ◽  
Spatio Temporal ◽  
On And Off Pathways ◽  
Game Theoretic Approach ◽  
Competing Pathways

Aggregation of amyloid- β (A β ) peptides is a significant event that underpins Alzheimer's disease (AD). A β aggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD pathogenesis. Therefore, there is increasing interest in understanding their formation and behaviour. In this paper, we use our previously established results on heterotypic interactions between A β and fatty acids (FAs) to investigate off-pathway aggregation under the control of FA concentrations to develop a mathematical framework that captures the mechanism. Our framework to define and simulate the competing on- and off-pathways of A β aggregation is based on the principles of game theory. Together with detailed simulations and biophysical experiments, our models describe the dynamics involved in the mechanisms of A β aggregation in the presence of FAs to adopt multiple pathways. Specifically, our reduced-order computations indicate that the emergence of off- or on-pathway aggregates are tightly controlled by a narrow set of rate constants, and one could alter such parameters to populate a particular oligomeric species. These models agree with the detailed simulations and experimental data on using FA as a heterotypic partner to modulate the temporal parameters. Predicting spatio-temporal landscape along competing pathways for a given heterotypic partner such as lipids is a first step towards simulating scenarios in which the generation of specific ‘conformer strains’ of A β could be predicted. This approach could be significant in deciphering the mechanisms of amyloid aggregation and strain generation, which are ubiquitously observed in many neurodegenerative diseases.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

Insights into amyloid disease from fly models

2014 ◽  
Vol 56 ◽  
pp. 69-83 ◽  
Author(s):  
Ko-Fan Chen ◽  
Damian C. Crowther
Keyword(s):  
Drosophila Melanogaster ◽  
Neurodegenerative Disorders ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Disease Pathogenesis ◽  
Amyloid Aggregates ◽  
Aβ Amyloid ◽  
Polypeptide Chains ◽  
Amyloid Diseases

The formation of amyloid aggregates is a feature of most, if not all, polypeptide chains. In vivo modelling of this process has been undertaken in the fruitfly Drosophila melanogaster with remarkable success. Models of both neurological and systemic amyloid diseases have been generated and have informed our understanding of disease pathogenesis in two main ways. First, the toxic amyloid species have been at least partially characterized, for example in the case of the Aβ (amyloid β-peptide) associated with Alzheimer's disease. Secondly, the genetic underpinning of model disease-linked phenotypes has been characterized for a number of neurodegenerative disorders. The current challenge is to integrate our understanding of disease-linked processes in the fly with our growing knowledge of human disease, for the benefit of patients.

Folate and vitamin B-12 deficiencies additively impaired memory function and disturbed the gut microbiota in amyloid-β infused rats

2019 ◽  
pp. 1-13 ◽  
Author(s):  
Sunmin Park ◽  
Sunna Kang ◽  
Da Sol Kim
Keyword(s):  
Insulin Resistance ◽  
Gut Microbiota ◽  
Insulin Signaling ◽  
Gut Microbiome ◽  
Metabolic Diseases ◽  
Memory Function ◽  
Amyloid Β ◽  
Impaired Memory ◽  
Ca1 Region ◽  
Folate And Vitamin B12

Abstract. Folate and vitamin B12(V-B12) deficiencies are associated with metabolic diseases that may impair memory function. We hypothesized that folate and V-B12 may differently alter mild cognitive impairment, glucose metabolism, and inflammation by modulating the gut microbiome in rats with Alzheimer’s disease (AD)-like dementia. The hypothesis was examined in hippocampal amyloid-β infused rats, and its mechanism was explored. Rats that received an amyloid-β(25–35) infusion into the CA1 region of the hippocampus were fed either control(2.5 mg folate plus 25 μg V-B12/kg diet; AD-CON, n = 10), no folate(0 folate plus 25 μg V-B12/kg diet; AD-FA, n = 10), no V-B12(2.5 mg folate plus 0 μg V-B12/kg diet; AD-V-B12, n = 10), or no folate plus no V-B12(0 mg folate plus 0 μg V-B12/kg diet; AD-FAB12, n = 10) in high-fat diets for 8 weeks. AD-FA and AD-VB12 exacerbated bone mineral loss in the lumbar spine and femur whereas AD-FA lowered lean body mass in the hip compared to AD-CON(P < 0.05). Only AD-FAB12 exacerbated memory impairment by 1.3 and 1.4 folds, respectively, as measured by passive avoidance and water maze tests, compared to AD-CON(P < 0.01). Hippocampal insulin signaling and neuroinflammation were attenuated in AD-CON compared to Non-AD-CON. AD-FAB12 impaired the signaling (pAkt→pGSK-3β) and serum TNF-α and IL-1β levels the most among all groups. AD-CON decreased glucose tolerance by increasing insulin resistance compared to Non-AD-CON. AD-VB12 and AD-FAB12 increased insulin resistance by 1.2 and 1.3 folds, respectively, compared to the AD-CON. AD-CON and Non-AD-CON had a separate communities of gut microbiota. The relative counts of Bacteroidia were lower and those of Clostridia were higher in AD-CON than Non-AD-CON. AD-FA, but not V-B12, separated the gut microbiome community compared to AD-CON and AD-VB12(P = 0.009). In conclusion, folate and B-12 deficiencies impaired memory function by impairing hippocampal insulin signaling and gut microbiota in AD rats.

Analytical methods to explore Amyloid-β-Peptide variants beyond Aβ1-40 and Aβ1-42

2015 ◽  
Vol 48 (06) ◽  
Author(s):  
H Esselmann ◽  
C Hafermann ◽  
O Jahn ◽  
I Kraus ◽  
J Vogelgsang ◽  
...  
Keyword(s):  
Analytical Methods ◽  
Amyloid Β ◽  
Amyloid Β Peptide
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