发表机构
North Carolina State University（北卡罗来纳州立大学）
机构由 AI 辅助整理，请以论文原文为准。AI 中文总结
该模型预测 tau 催化 A$\beta$ 成核可提高寡聚体负担而不增加斑块体积，揭示二者解耦，且效应需神经元裂解形成鬼缠结，并受解离和周转抑制。
AI 中文摘要
tau 蛋白和淀粉样-β（A$\beta$）沉积物在阿尔茨海默病中共同出现，且最近体外实验表明 tau 纤维能以折叠特异性方式催化 A$\beta$ 初级成核。本文开发了一个双区室动力学模型，描述神经元胞体内的 tau 聚集以及周围间质中的 A$\beta$ 聚集。可调节的耦合参数是体细胞 tau 纤维物质中可被间质 A$\beta$ 接触的部分分数 f$_{acc}$。同型 A$\beta$ 二次成核被限制在固化斑块的可接触表面，而非随总纤维质量缩放，这既保持了速率常数的体外校准，又防止表面项在数十年间无界增长。模型产生三个预测。第一，模型预测 tau 催化的成核可将可溶性 A$\beta$ 寡聚体浓度和 A$\beta$ 纤维种类数量分别提高 4.6 倍和 2.0 倍（在完全可接触时），同时保持总 A$\beta$ 纤维质量和斑块体积不变，因为在无清除的情况下这些由单体供应决定；因此寡聚体负担和可见斑块负担被解耦。第二，预测效应需要显著的可接触性：累积寡聚体暴露增加 50% 需要 f$_{acc}$ $\approx$ 0.035-0.15，这难以与完整神经元膜包裹的缠结相协调，而指向神经元裂解和细胞外鬼缠结的形成。第三，生理相关的寡聚体解离和蛋白水解周转分别将累积暴露抑制约三个数量级和（在零 tau 可接触性时）约七十倍，并完全消除对生物学年龄测量的影响。
英文摘要
Tau and amyloid-$β$ (A$β$) deposits co-occur in Alzheimer's disease, and tau fibrils have recently been shown in vitro to catalyze A$β$ primary nucleation in a fold-specific manner. A two-compartment kinetic model is developed here, describing tau aggregation within the neuronal soma and A$β$ aggregation in the surrounding interstitium. The adjustable coupling parameter is the fraction f$_{acc}$ of somatic tau fibrillar material accessible to interstitial A$β$. Homotypic A$β$ secondary nucleation is restricted to the accessible surface of the consolidating plaque rather than scaling with total fibril mass, which preserves the in vitro calibration of the rate constant while preventing the surface term from growing without bound over decades. Three model predictions emerge. First, the model predicts that tau-catalyzed nucleation can increase the soluble A$β$ oligomer concentration and the number of A$β$ fibrillar species, by factors of 4.6 and 2.0, respectively, at complete accessibility, while leaving total A$β$ fibril mass and plaque volume unchanged, since in the absence of clearance these are fixed by the monomer supply; oligomer burden and visible plaque burden are therefore decoupled. Second, the predicted effect requires substantial accessibility: a 50 % increase in accumulated oligomer exposure needs f$_{acc}$ $\approx$ 0.035-0.15, which is difficult to reconcile with tangles enclosed by an intact neuronal membrane and points instead to neuronal lysis and the formation of extracellular ghost tangles. Third, physiologically relevant oligomer dissociation and proteolytic turnover each suppress accumulated exposure, by approximately three orders of magnitude and, at zero tau accessibility, about seventyfold, respectively, and remove the effect on a biological-age measure entirely.
