{"title":"Dynamics of waste proteins in brain tissue: Numerical insights into Alzheimer's risk factors","authors":"Lily Watkins, Saikat Mukherjee, Jeffrey Tithof","doi":"10.1103/physreve.110.034401","DOIUrl":null,"url":null,"abstract":"Over the past few decades, research has indicated that the buildup of waste proteins, like amyloid-<math xmlns=\"http://www.w3.org/1998/Math/MathML\"><mi>β</mi></math> (<math xmlns=\"http://www.w3.org/1998/Math/MathML\"><mrow><mi mathvariant=\"normal\">A</mi><mi>β</mi></mrow></math>), in the brain's interstitial spaces is linked to neurodegenerative diseases like Alzheimer's, but the details of how such proteins are removed from the brain are not well understood. We have developed a numerical model to investigate the aggregation and clearance mechanisms of <math xmlns=\"http://www.w3.org/1998/Math/MathML\"><mrow><mi mathvariant=\"normal\">A</mi><mi>β</mi></mrow></math> in the interstitial spaces of the brain. The model describes the volume-averaged transport of <math xmlns=\"http://www.w3.org/1998/Math/MathML\"><mrow><mi mathvariant=\"normal\">A</mi><mi>β</mi></mrow></math> in a segment of the brain interstitium modeled as a porous medium, oriented between the perivascular space (fluid-filled channel surrounding a blood vessel) of a penetrating arteriole and that of a venule. Our numerical approach solves <math xmlns=\"http://www.w3.org/1998/Math/MathML\"><mi>N</mi></math> coupled advection-diffusion-aggregation equations that model the production, aggregation, fragmentation, and clearance of <math xmlns=\"http://www.w3.org/1998/Math/MathML\"><mi>N</mi></math> species of <math xmlns=\"http://www.w3.org/1998/Math/MathML\"><mrow><mi mathvariant=\"normal\">A</mi><mi>β</mi></mrow></math>. We simulate <math xmlns=\"http://www.w3.org/1998/Math/MathML\"><mrow><mi>N</mi><mo>=</mo><mn>50</mn></mrow></math> species to investigate the oligomer-size dependence of clearance and aggregation. We introduce a timescale plot that helps predict <math xmlns=\"http://www.w3.org/1998/Math/MathML\"><mrow><mi mathvariant=\"normal\">A</mi><mi>β</mi></mrow></math> buildup for different neurological conditions. We show that a sudden increase in monomer concentration, as occurs in conditions like traumatic brain injury, leads to significant plaque formation, which can qualitatively be predicted using the timescale plot. Our results also indicate that impaired protein clearance (as occurs with aging) and fragmentation are both mechanisms that sustain large intermediate oligomer concentrations. Our results provide novel insight into several known risk factors for Alzheimer's disease and cognitive decline, and we introduce a unique framing of <math xmlns=\"http://www.w3.org/1998/Math/MathML\"><mrow><mi mathvariant=\"normal\">A</mi><mi>β</mi></mrow></math> dynamics as a competition between different timescales associated with production rates, aggregation rates, and clearance conditions.","PeriodicalId":20085,"journal":{"name":"Physical review. E","volume":null,"pages":null},"PeriodicalIF":2.4000,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Physical review. E","FirstCategoryId":"101","ListUrlMain":"https://doi.org/10.1103/physreve.110.034401","RegionNum":3,"RegionCategory":"物理与天体物理","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Mathematics","Score":null,"Total":0}
引用次数: 0
Abstract
Over the past few decades, research has indicated that the buildup of waste proteins, like amyloid- (), in the brain's interstitial spaces is linked to neurodegenerative diseases like Alzheimer's, but the details of how such proteins are removed from the brain are not well understood. We have developed a numerical model to investigate the aggregation and clearance mechanisms of in the interstitial spaces of the brain. The model describes the volume-averaged transport of in a segment of the brain interstitium modeled as a porous medium, oriented between the perivascular space (fluid-filled channel surrounding a blood vessel) of a penetrating arteriole and that of a venule. Our numerical approach solves coupled advection-diffusion-aggregation equations that model the production, aggregation, fragmentation, and clearance of species of . We simulate species to investigate the oligomer-size dependence of clearance and aggregation. We introduce a timescale plot that helps predict buildup for different neurological conditions. We show that a sudden increase in monomer concentration, as occurs in conditions like traumatic brain injury, leads to significant plaque formation, which can qualitatively be predicted using the timescale plot. Our results also indicate that impaired protein clearance (as occurs with aging) and fragmentation are both mechanisms that sustain large intermediate oligomer concentrations. Our results provide novel insight into several known risk factors for Alzheimer's disease and cognitive decline, and we introduce a unique framing of dynamics as a competition between different timescales associated with production rates, aggregation rates, and clearance conditions.
期刊介绍:
Physical Review E (PRE), broad and interdisciplinary in scope, focuses on collective phenomena of many-body systems, with statistical physics and nonlinear dynamics as the central themes of the journal. Physical Review E publishes recent developments in biological and soft matter physics including granular materials, colloids, complex fluids, liquid crystals, and polymers. The journal covers fluid dynamics and plasma physics and includes sections on computational and interdisciplinary physics, for example, complex networks.