Dataset Information

Mathematical Model Shows How Sleep May Affect Amyloid-? Fibrillization.

ABSTRACT: Deposition of amyloid-? (A?) fibers in the extracellular matrix of the brain is a ubiquitous feature associated with several neurodegenerative disorders, especially Alzheimer's disease (AD). Although many of the biological aspects that contribute to the formation of A? plaques are well addressed at the intra- and intercellular levels in short timescales, an understanding of how A? fibrillization usually starts to dominate at a longer timescale despite the presence of mechanisms dedicated to A? clearance is still lacking. Furthermore, no existing mathematical model integrates the impact of diurnal neural activity as emanated from circadian regulation to predict disease progression due to a disruption in the sleep-wake cycle. In this study, we develop a minimal model of A? fibrillization to investigate the onset of AD over a long timescale. Our results suggest that the diseased state is a manifestation of a phase change of the system from soluble A? (sA?) to fibrillar A? (fA?) domination upon surpassing a threshold in the production rate of sA?. By incorporating the circadian rhythm into our model, we reveal that fA? accumulation is crucially dependent on the regulation of the sleep-wake cycle, thereby indicating the importance of good sleep hygiene in averting AD onset. We also discuss potential intervention schemes to reduce fA? accumulation in the brain by modification of the critical sA? production rate.

SUBMITTER: Hoore M

PROVIDER: S-EPMC7451937 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Mathematical Model Shows How Sleep May Affect Amyloid-β Fibrillization.

Hoore Masoud M Khailaie Sahamoddin S Montaseri Ghazal G Mitra Tanmay T Meyer-Hermann Michael M

Biophysical journal 20200722 4

Deposition of amyloid-β (Aβ) fibers in the extracellular matrix of the brain is a ubiquitous feature associated with several neurodegenerative disorders, especially Alzheimer's disease (AD). Although many of the biological aspects that contribute to the formation of Aβ plaques are well addressed at the intra- and intercellular levels in short timescales, an understanding of how Aβ fibrillization usually starts to dominate at a longer timescale despite the presence of mechanisms dedicated to Aβ c ...[more]

PMID: 32758420

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Project description:The chemical and physical mechanisms by which gyrating beads accelerate amyloid fibrillization in microtiter plate assays are unclear. Identifying these mechanisms will help optimize high-throughput screening assays for molecules and mutations that modulate aggregation and might explain why different research groups report different rates of aggregation for identical proteins. This article investigates how the rate of superoxide dismutase-1 (SOD1) fibrillization is affected by 12 different beads with a wide range of hydrophobicity, mass, stiffness, and topology but identical diameter. All assays were performed on D90A apo-SOD1, which is a stable and wild-type-like variant of SOD1. The most significant and uniform correlation between any material property of each bead and that bead's effect on SOD1 fibrillization rate was with regard to bead mass. A linear correlation existed between bead mass and rate of fibril elongation (R2 = 0.7): heavier beads produced faster rates and shorter fibrils. Nucleation rates (lag time) also correlated with bead mass, but only for non-polymeric beads (i.e., glass, ceramic, metallic). The effect of bead mass on fibrillization correlated (R2 = 0.96) with variations in buoyant forces and contact forces (between bead and microplate well), and was not an artifact of residual momentum during intermittent gyration. Hydrophobic effects were observed, but only for polymeric beads: lag times correlated negatively with contact angle of water and degree of protein adhesion (surface adhesion and hydrophobic effects were negligible for non-polymeric beads). These results demonstrate that contact forces (alone) explain kinetic variation among non-polymeric beads, whereas surface hydrophobicity and contact forces explain kinetic variation among polymeric beads. This study also establishes conditions for high-throughput amyloid assays of SOD1 that enable the control over fibril morphologies and produce eightfold faster lag times and fourfold less stochasticity than in previous studies.

Dataset Information

Mathematical Model Shows How Sleep May Affect Amyloid-? Fibrillization.

Publications

Mathematical Model Shows How Sleep May Affect Amyloid-β Fibrillization.

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