Epidemic Spreading Model to Characterize Misfolded Proteins Propagation in Aging and Associated Neurodegenerative Disorders
Epidemic Spreading Model to Characterize Misfolded Proteins Propagation in Aging and Associated Neurodegenerative Disorders
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DOI：
10.1371/journal.pcbi.1003956
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发表时间：
2014-11-01
影响因子：
4.3
通讯作者：
Evans, Alan C.
中科院分区：
文献类型：
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作者：
Iturria-Medina, Yasser;Sotero, Roberto C.;Evans, Alan C.
错折叠蛋白(MP)是衰老和相关的神经退行性疾病的关键成分。例如，错误折叠的淀粉样β蛋白(Aβ)和tau蛋白是阿尔茨海默病的两个神经致病特征。脑内MP传播/沉积的潜在机制基本上仍不清楚。在这里，介绍了MP动力学的流行病传播模型(ESM)，该模型考虑了MP毒剂之间的传播式相互作用和大脑通过结构连接体的清除反应。ESM在人脑中复制了高级Aβ沉积模式(解释了ADNI数据库中733名受试者局部Aβ负荷变化的46%，类似于56%)。此外，该模型有力地支持了a)Aβ清除缺陷和Aβ早期发病年龄在阿尔茨海默病进展中的主导作用，b)距离Aβ暴发区域的有效解剖距离解释了局部Aβ到达时间和Aβ沉积可能性，c)APOE e4基因、性别和教育水平对终生脑内Aβ传播的多因素影响，以及d)Aβ传播历史对tau蛋白浓度的调制影响，支持了Aβ病理生理学和tau病之间相互关联的途径的假说。据我们所知，ESM是第一个强调结构大脑网络结构、致病蛋白的产生/清除和相关的细胞间转移机制、个体遗传/人口统计特性以及健康和疾病临床状态之间的直接联系的计算模型。总之，拟议的ESM构成了一个有希望的框架，以阐明与衰老和神经退行性疾病相关的脑内区域到区域转移机制。
Misfolded proteins (MP) are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-beta (A beta) and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intrabrain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM) for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced A beta deposition patterns in the human brain (explaining 46 similar to 56% of the variance in regional A beta loads, in 733 subjects from the ADNI database). Furthermore, this model strongly supports a) the leading role of A beta clearance deficiency and early A beta onset age during Alzheimer's disease progression, b) that effective anatomical distance from A beta outbreak region explains regional A beta arrival time and A beta deposition likelihood, c) the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain A beta propagation, and d) the modulatory impact of A beta propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between A beta pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders.