The effects of microglia on tauopathy progression can be quantified using Nexopathy in silico (Nexis) models.
The effects of microglia on tauopathy progression can be quantified using Nexopathy in silico (Nexis) models.
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DOI：
10.1038/s41598-022-25131-3
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发表时间：
2022-12-07
影响因子：
4.6
通讯作者：
Raj, Ashish
中科院分区：
文献类型：
--
作者：
Anand, Chaitali;Maia, Pedro D.;Torok, Justin;Mezias, Christopher;Raj, Ashish
之前已经使用基于连接体的网络扩散模型对错误折叠的tau蛋白沿着大脑连接体的朊病毒样跨突触传播进行了建模。除了连接体之外，神经退行性脑中的一般神经学“环境”与蛋白质病变物种之间的相互作用也可有助于病理传播。这种分子nexopathy框架假定，神经退行性疾病的独特特征源于网络和周围分子参与者之间的相互作用。然而，这些调节剂的作用仍然是不可量化的。在这里，我们提出了Nexopathy in silico（“Nexis”），这是一种tau进展的定量模型，通过包括由基于连接体的扩散的分子调节剂定义的病理传播参数来增强早期模型。我们的Nexis：小胶质细胞模型通过纳入小胶质细胞的影响扩展了以前的神经病理学进展模型，首次定量表征了这种对全脑的影响。我们发现Trem2，而不是小胶质细胞稳态基因，显着提高了模型的预测能力。Trem2似乎降低了tau的积累率，同时增加了其从海马种子区的区域间扩散，导致纹状体、苍白球和对侧海马中的tau负荷更高。Nexis提供了对小胶质细胞对tau传播的贡献的更好理解和量化，并且可以灵活地进行修改以包括进行性神经变性的其他调节剂。
The prion-like transsynaptic propagation of misfolded tau along the brain’s connectome has previously been modeled using connectome-based network diffusion models. In addition to the connectome, interactions between the general neurological “milieu” in the neurodegenerative brain and proteinopathic species can also contribute to pathology propagation. Such a molecular nexopathy framework posits that the distinct characteristics of neurodegenerative disorders stem from interactions between the network and surrounding molecular players. However, the effects of these modulators remain unquantified. Here, we present Nexopathy in silico (“Nexis”), a quantitative model of tau progression augmenting earlier models by including parameters of pathology propagation defined by the molecular modulators of connectome-based spread. Our Nexis:microglia model provides the first quantitative characterization of this effect on the whole brain by expanding previous models of neuropathology progression by incorporating microglial influence. We show that Trem2, but not microglial homeostasis genes, significantly improved the model’s predictive power. Trem2 appears to reduce tau accumulation rate while increasing its interregional spread from the hippocampal seed area, causing higher tau burden in the striatum, pallidum, and contralateral hippocampus. Nexis provides an improved understanding and quantification of microglial contribution to tau propagation and can be flexibly modified to include other modulators of progressive neurodegeneration.
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影响因子：
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