迈向阿尔茨海默病的整合理论:连接神经毒性、β -淀粉样蛋白生物标志物和诊断的分子机制。

IF 1.8 4区 医学 Q3 CLINICAL NEUROLOGY
Yaroslav I Molkov, Maria V Zaretskaia, Dmitry V Zaretsky
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引用次数: 0

摘要

淀粉样蛋白为中心的阿尔茨海默病(AD)理论的一个主要空白是,尽管淀粉样蛋白原纤维本身在体外没有毒性,但AD的诊断显然与β -淀粉样蛋白(Aβ)沉积物的密度相关。基于我们提出的淀粉样蛋白降解毒性假设,我们开发了一个数学模型来解释这种差异。这表明细胞毒性取决于细胞对可溶性Aβ的摄取,而不是淀粉样蛋白聚集体的存在。脑脊液(CSF)中可溶性β -淀粉样蛋白的动力学和a- β沉积物的密度是用微分方程系统描述的。在该模型中,细胞毒性损伤与细胞摄取Aβ成正比,而AD诊断的概率由疾病持续时间内积累的Aβ细胞毒性来定义。摄取后,Aβ在溶酶体内被浓缩,促进细胞内纤颤种子的形成。这些种子不能被消化,要么积聚在细胞内,要么排出细胞。Aβ开始聚集在细胞外种子上,因此,间质液中的浓度降低。Aβ的毒性和聚集依赖于相同的过程-细胞摄取Aβ-解释了AD诊断与大脑中淀粉样蛋白聚集密度之间的相关性。方法:我们使用从阿尔茨海默病神经影像学倡议(ADNI)获得的临床数据来测试模型,其中包括脑脊液中β -淀粉样蛋白浓度(csf -a - β42)的记录和使用正电子发射断层扫描(PET)测量的β -淀粉样蛋白沉积密度。该模型以csf - a - β42和PET的函数预测AD诊断的概率,并在95%的置信度下拟合实验数据。结果:我们的研究表明,现有的临床数据允许对描述β -淀粉样蛋白转换和疾病进展的动力学参数进行推断。csf - a - β42和PET值的每种组合可用于计算个体的细胞摄取速率、有效疾病持续时间和累积毒性。我们表明,这些参数的自然限制解释了这两种生物标志物在人群中临床数据集的特征分布。结论:由此得出的数学模型解释了Aβ沉积密度与AD诊断概率之间的正相关关系,而无需假设聚集的β -淀粉样蛋白具有任何细胞毒性。据我们所知,该模型是第一个从机制上解释脑脊液中Aβ42浓度与AD诊断概率之间的负相关关系的模型。最后,基于淀粉样蛋白降解毒性假说和数学模型提供的见解,我们提出了新的病理生理相关的生物标志物来诊断和预测AD。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Towards the Integrative Theory of Alzheimer's Disease: Linking Molecular Mechanisms of Neurotoxicity, Beta-amyloid Biomarkers, and the Diagnosis.

Introduction: A major gap in amyloid-centric theories of Alzheimer's disease (AD) is that even though amyloid fibrils per se are not toxic in vitro, the diagnosis of AD clearly correlates with the density of beta-amyloid (Aβ) deposits. Based on our proposed amyloid degradation toxicity hypothesis, we developed a mathematical model explaining this discrepancy. It suggests that cytotoxicity depends on the cellular uptake of soluble Aβ rather than on the presence of amyloid aggregates. The dynamics of soluble beta-amyloid in the cerebrospinal fluid (CSF) and the density of Aβ deposits is described using a system of differential equations. In the model, cytotoxic damage is proportional to the cellular uptake of Aβ, while the probability of an AD diagnosis is defined by the Aβ cytotoxicity accumulated over the duration of the disease. After uptake, Aβ is concentrated intralysosomally, promoting the formation of fibrillation seeds inside cells. These seeds cannot be digested and are either accumulated intracellularly or exocytosed. Aβ starts aggregating on the extracellular seeds and, therefore, decreases in concentration in the interstitial fluid. The dependence of both Aβ toxicity and aggregation on the same process-cellular uptake of Aβ-explains the correlation between AD diagnosis and the density of amyloid aggregates in the brain.

Methods: We tested the model using clinical data obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI), which included records of beta-amyloid concentration in the cerebrospinal fluid (CSF-Aβ42) and the density of beta-amyloid deposits measured using positron emission tomography (PET). The model predicts the probability of AD diagnosis as a function of CSF-Aβ42 and PET and fits the experimental data at the 95% confidence level.

Results: Our study shows that existing clinical data allows for the inference of kinetic parameters describing beta-amyloid turnover and disease progression. Each combination of CSF-Aβ42 and PET values can be used to calculate the individual's cellular uptake rate, the effective disease duration, and the accumulated toxicity. We show that natural limitations on these parameters explain the characteristic distribution of the clinical dataset for these two biomarkers in the population.

Conclusion: The resulting mathematical model interprets the positive correlation between the density of Aβ deposits and the probability of an AD diagnosis without assuming any cytotoxicity of the aggregated beta-amyloid. To the best of our knowledge, this model is the first to mechanistically explain the negative correlation between the concentration of Aβ42 in the CSF and the probability of an AD diagnosis. Finally, based on the amyloid degradation toxicity hypothesis and the insights provided by mathematical modeling, we propose new pathophysiology-relevant biomarkers to diagnose and predict AD.

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来源期刊
Current Alzheimer research
Current Alzheimer research 医学-神经科学
CiteScore
4.00
自引率
4.80%
发文量
64
审稿时长
4-8 weeks
期刊介绍: Current Alzheimer Research publishes peer-reviewed frontier review, research, drug clinical trial studies and letter articles on all areas of Alzheimer’s disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer’s disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer’s disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer''s disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer’s disease. Current Alzheimer Research provides a comprehensive ''bird''s-eye view'' of the current state of Alzheimer''s research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.
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