Simulating the effect of formation of amyloid plaques on aggregation of tau protein
Simulating the effect of formation of amyloid plaques on aggregation of tau protein
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DOI：
10.1098/rspa.2018.0511
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发表时间：
2018-12-01
影响因子：
3.5
通讯作者：
Kuznetsov, A. V.
中科院分区：
文献类型：
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作者：
Kuznetsov, I. A.;Kuznetsov, A. V.
在本文中，我们建立了一个数学模型，能够研究神经元中淀粉样前体蛋白(APP)和tau蛋白的产生和细胞内运输。我们还研究了APP片段聚集成淀粉样β蛋白(Aβ)以及tau聚集成tau寡聚体和神经原纤维缠结。使用开发的模型，我们研究了Aβ聚集如何影响tau在胞体和轴突中的运输和聚集。我们通过假设描述tau聚集的自催化生长(自复制)反应步骤的动力学常数的值与Aβ浓度成正比来耦合Aβ和tau聚集过程。该模型预测，APP和tau在轴突中的分布不同。虽然APP在轴突上的分布是均匀的，但tau的浓度先是减少，然后朝着突触增加。β蛋白沿着轴突均匀产生，而错误折叠的tau蛋白主要在近端轴突产生。起源于轴突的Aβ和tau聚合物的数量比起源于胞体的Aβ和tau聚合物的数量少得多。错误折叠的tau聚合物的生产速度取决于Aβ对其生产的促进程度。
In this paper, we develop a mathematical model that enables the investigation of the production and intracellular transport of amyloid precursor protein (APP) and tau protein in a neuron. We also investigate the aggregation of APP fragments into amyloid-beta (A beta) as well as tau aggregation into tau oligomers and neurofibrillary tangles. Using the developed model, we investigate how A beta aggregation can influence tau transport and aggregation in both the soma and the axon. We couple the A beta and tau agglomeration processes by assuming that the value of the kinetic constant that describes the autocatalytic growth (self-replication) reaction step of tau aggregation is proportional to the A beta concentration. The model predicts that APP and tau are distributed differently in the axon. While APP has a uniform distribution along the axon, tau's concentration first decreases and then increases towards the synapse. A beta is uniformly produced along the axon while misfolded tau protein is mostly produced in the proximal axon. The number of A beta and tau polymers originating from the axon is much smaller than the number of A beta and tau polymers originating from the soma. The rate of production of misfolded tau polymers depends on how strongly their production is facilitated by A beta.