Dynamics of prion proliferation under combined treatment of pharmacological chaperones and interferons

Garzón, Doménica N.; Castillo, Yair; Navas-Zuloaga, M. Gabriela; Darwin, Leah; Hardin, Abigail; Culik, Nora; Yang, Anji; Castillo-Garsow, Carlos; Rı́os-Soto, Karen R.; Arriola, Leon; Ghosh, Aditi

doi:10.1016/j.jtbi.2021.110797

Cited by 5 publications

(4 citation statements)

References 32 publications

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“…Proteinopathy dynamics are described by the heterodimer model, one of the most common hypotheses that describe the prion-like spreading of toxic proteins. This hypothesis suggests that a healthy (properly folded) protein misfolds when it interacts with a toxic version of itself (misfolded; the prion/seed) following the latter’s structure as a template (Garzón et al, 2021). Therefore, this model includes healthy and toxic versions of amyloid-beta ( Aβ / Aβt ) and tau (TAU/TAUt) that are produced, cleared, trans-formed (from healthy to toxic), and propagated in the SC with N nodes.…”

Section: Methodsmentioning

confidence: 99%

A multiscale closed-loop neurotoxicity model of Alzheimer’s disease progression explains functional connectivity alterations

Cabrera-Álvarez,

Stefanovski,

Martin

et al. 2023

Preprint

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While the accumulation of amyloid-beta (Aβ) and hyperphosphorylated-tau (hp-tau) as two classical histopathological biomarkers are crucial in Alzheimer's disease (AD), their detailed interaction with the electrophysiological changes at the meso- and macroscale are not yet fully understood. We developed a mechanistic multiscale model of AD progression, linking proteinopathy to its effects on neural activity and vice-versa. We integrated a heterodimer model of prion-like protein propagation, and a network of Jansen-Rit electrical oscillators whose model parameters varied due to neurotoxicity. Changes in inhibition guided the electrophysiological alterations found in AD, and both Aβ and hp-tau-related inhibition changes were able to produce similar effects independently. Additionally, we found a causal disconnection between cellular hyperactivity and interregional hypersynchrony. Finally, we demonstrated that early Aβ and hp-tau depositions' location determine the spatiotemporal profile of the proteinopathy. The presented model combines the molecular effects of both Aβ and hp-tau together with a mechanistic protein propagation model and network effects within a unique closed-loop model. This holds the potential to enlighten the interplay between AD mechanisms on various scales, aiming to develop and test novel hypotheses on the contribution of different AD-related variables to the disease evolution.

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Section: Methodsmentioning

confidence: 99%

A multiscale closed-loop neurotoxicity model of Alzheimer’s disease progression explains functional connectivity alterations

Cabrera-Álvarez,

Stefanovski,

Martin

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…the prion/seed) following the latter's structure as a template (Garzón et al, 2021). Therefore, this model includes healthy and toxic versions of amyloidbeta (Aβ, Ãβ) and tau (T , T ) that are produced, cleared, transformed (from healthy to toxic), and propagated in the SC with N nodes.…”

Section: Brain Network Modelmentioning

confidence: 99%

A Multiscale Closed-Loop Neurotoxicity Model of Alzheimer’s Disease Progression Explains Functional Connectivity Alterations

Cabrera-Álvarez,

Stefanovski,

Martin

et al. 2024

eNeuro

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The accumulation of amyloid-beta (Αβ) and hyperphosphorylated-tau (hp-tau) are two classical histopathological biomarkers in Alzheimer's disease (AD). However, their detailed interactions with the electro physiological changes at the meso- and macroscale are not yet fully understood. We developed a mechanistic multiscale model of AD progression, linking proteinopathy to its effects on neural activity and vice-versa. We integrated a heterodimer model of prion-like protein propagation, and a brain network model of Jansen-Rit neural masses derived from human neuroimaging data whose parameters varied due to neurotoxicity. Results showed that changes in inhibition guided the electrophysiological alterations found in AD, and these changes were mainly attributed to Αβ effects. Additionally, we found a causal disconnection between cellular hyperactivity and interregional hypersynchrony contrary to previous beliefs. Finally, we demonstrated that early Αβ and hp-tau depositions’ location determine the spatiotemporal profile of the proteinopathy. The presented model combines the molecular effects of both Αβ and hp-tau together with a mechanistic protein propagation model and network effects within a closed-loop model. This holds the potential to enlighten the interplay between AD mechanisms on various scales, aiming to develop and test novel hypotheses on the contribution of different AD-related variables to the disease evolution.Significance StatementThis research presents a closed-loop model of AD mechanisms, bridging the gap between protein distribution and neural activity. Contrary to prior beliefs, the study reveals that interregional hypersynchrony and cellular hyperactivity are not directly linked. Notably, the model identifies neural inhibition as a potential causal factor in neurophysiological AD alterations and posits early depositions of Aβ as a determinant of the spatiotemporal profile of proteinopathy. The significance of this mechanistic disease framework lies in its potential to produce insights into AD evolution and to guide novel treatment strategies. It underscores the importance of further experiments and modelling efforts to refine our understanding of AD, offering hope for more effective treatments and personalized care in the fight against dementia.

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“…Several prion proliferation models are developed and studied; see earlier works [1][2][3][4][5][6][7][8][9][10][11]. There are pharmacological, chemical, and molecular chaperones [12,13], that inhibit the growth of infectious agents and therefore can be considered as a potential therapeutic agent. These chaperones are effective in preventing misfolding of various disease-causing proteins, thereby reducing the severity of several neurodegenerative disorders and other protein-misfolding diseases such as prion diseases.…”

Section: Introductionmentioning

confidence: 99%

“…Chaperones are considered promising therapeutic agents against degenerative diseases, including neurodegenerative disorders like as transmissible spongiform encephalopathy (TSE), and play a significant role to inhibit the production of infectious agents. The dynamics of prion proliferation under combined treatment of interferons and pharmacological chaperones is studied in Garzón et al [12]. Also, the impact of both treatments on prion population is discussed.…”

Section: Introductionmentioning

confidence: 99%

Analysis of a prion proliferation model with polymer coagulation in the presence of chaperone

Choudhary

Kumar

2023

Math Methods in App Sciences

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In the present work, a mathematical model which consists of a nonlinear partial integro-differential equation coupled with two ordinary differential equations (ODEs) is analyzed. This model describes the relation between infectious, noninfectious prion proteins, and chaperone. The well-posedness of the system is proved for bounded kernels by using evolution operator theory in the state space R×R×L 1 (Z, zdz). The existence of a global weak solution for unbounded kernels is also discussed by a weak compactness argument. In addition, we investigated the stability analysis results theoretically and effect of chaperone on prion proliferation numerically.

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Dynamics of prion proliferation under combined treatment of pharmacological chaperones and interferons

Cited by 5 publications

References 32 publications

A multiscale closed-loop neurotoxicity model of Alzheimer’s disease progression explains functional connectivity alterations

A multiscale closed-loop neurotoxicity model of Alzheimer’s disease progression explains functional connectivity alterations

A Multiscale Closed-Loop Neurotoxicity Model of Alzheimer’s Disease Progression Explains Functional Connectivity Alterations

Analysis of a prion proliferation model with polymer coagulation in the presence of chaperone

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