Interactions of Therapeutic Antibodies With Presynaptically-Released Misfolded Proteins in Neurodegenerative Diseases. A Spatial Monte-Carlo Simulation Study.

IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Jamie Goff, Maryam Khalifa, Shaina M Short, Piet H van der Graaf, Hugo Geerts
{"title":"Interactions of Therapeutic Antibodies With Presynaptically-Released Misfolded Proteins in Neurodegenerative Diseases. A Spatial Monte-Carlo Simulation Study.","authors":"Jamie Goff, Maryam Khalifa, Shaina M Short, Piet H van der Graaf, Hugo Geerts","doi":"10.1002/psp4.70035","DOIUrl":null,"url":null,"abstract":"<p><p>The spatial progression hypothesis of misfolded tau and alpha-synuclein proteins in Alzheimer's and Parkinson's Disease proposes the release of proteins from a presynaptic membrane followed by diffusion over the synaptic cleft and uptake by the postsynaptic membrane in the afferent neuron. A number of antibodies aiming to reduce this neuronal uptake by capturing these proteins in the extracellular space are currently in clinical development, so far without much success. For modeling the interaction between antibodies and misfolded proteins in the extremely small synaptic volume with only a few proteins navigating a crowded environment of transsynaptic proteins, traditional assumptions of ordinary differential equations (ODEs) break down. Here we use spatial Monte Carlo calculations of individual molecule trajectories in a realistic geometrical environment using the open-source software Mcell (mcell.org). For several different densities of transsynaptic proteins, we show that due to geometric constraints, less than 0.5% of the antibody in the brain interstitial fluid (ISF) can enter the crowded synaptic cleft. As a consequence, uptake of the seed-competent proteins is reduced by less than 10%, even at the highest concentration and for selective antibodies. Only the seed-competent protein that escapes the synaptic cleft (between 15% and 30%) is captured by the antibody. Given the extremely low penetrance of the antibodies, it is close to impossible for antibodies to interfere with the uptake mechanism that takes place in the synaptic cleft. These simulations using a detailed and realistic biological environment provide a possible explanation for the clinical trial failures of anti-tau and anti-αsynuclein antibodies.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"CPT: Pharmacometrics & Systems Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/psp4.70035","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

Abstract

The spatial progression hypothesis of misfolded tau and alpha-synuclein proteins in Alzheimer's and Parkinson's Disease proposes the release of proteins from a presynaptic membrane followed by diffusion over the synaptic cleft and uptake by the postsynaptic membrane in the afferent neuron. A number of antibodies aiming to reduce this neuronal uptake by capturing these proteins in the extracellular space are currently in clinical development, so far without much success. For modeling the interaction between antibodies and misfolded proteins in the extremely small synaptic volume with only a few proteins navigating a crowded environment of transsynaptic proteins, traditional assumptions of ordinary differential equations (ODEs) break down. Here we use spatial Monte Carlo calculations of individual molecule trajectories in a realistic geometrical environment using the open-source software Mcell (mcell.org). For several different densities of transsynaptic proteins, we show that due to geometric constraints, less than 0.5% of the antibody in the brain interstitial fluid (ISF) can enter the crowded synaptic cleft. As a consequence, uptake of the seed-competent proteins is reduced by less than 10%, even at the highest concentration and for selective antibodies. Only the seed-competent protein that escapes the synaptic cleft (between 15% and 30%) is captured by the antibody. Given the extremely low penetrance of the antibodies, it is close to impossible for antibodies to interfere with the uptake mechanism that takes place in the synaptic cleft. These simulations using a detailed and realistic biological environment provide a possible explanation for the clinical trial failures of anti-tau and anti-αsynuclein antibodies.

治疗性抗体与突触前释放的错误折叠蛋白在神经退行性疾病中的相互作用。空间蒙特卡罗模拟研究。
阿尔茨海默病和帕金森病中错误折叠的tau和α -突触核蛋白的空间进展假说提出,蛋白质从突触前膜释放,随后扩散到突触间隙,并被传入神经元的突触后膜摄取。一些旨在通过在细胞外空间捕获这些蛋白质来减少这种神经元摄取的抗体目前正在临床开发中,到目前为止还没有太大的成功。为了在极小的突触体积中模拟抗体和错误折叠蛋白质之间的相互作用,只有少数蛋白质在拥挤的跨突触蛋白质环境中导航,传统的常微分方程假设(ode)被打破。在这里,我们使用空间蒙特卡罗计算单个分子轨迹在一个现实的几何环境中使用开源软件Mcell (mcell.org)。对于几种不同密度的跨突触蛋白,我们发现由于几何限制,在脑间质液(ISF)中只有不到0.5%的抗体可以进入拥挤的突触间隙。因此,即使在最高浓度和选择性抗体下,对种子敏感蛋白的摄取也减少了不到10%。只有能够逃脱突触间隙的种子蛋白(15% - 30%)才会被抗体捕获。鉴于抗体的外显率极低,抗体几乎不可能干扰发生在突触间隙中的摄取机制。这些模拟使用了详细和真实的生物环境,为抗tau和抗α突触核蛋白抗体的临床试验失败提供了可能的解释。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
5.00
自引率
11.40%
发文量
146
审稿时长
8 weeks
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信