BACKGROUND Autophagy is an evolutionarily conserved intracellular process that is used for delivering proteins and organelles to the lysosome for degradation. For decades, autophagy has been speculated to regulate amyloid-β peptide (Aβ) accumulation, which is involved in Alzheimer's disease (AD); however, specific autophagic effects on the Aβ kinetics only have begun to be explored. RESULTS We develop a mathematical model for autophagy with respect to Aβ kinetics and perform simulations to understand the quantitative relationship between Aβ levels and autophagy activity. In the case of an abnormal increase in the Aβ generation, the degradation, secretion, and clearance rates of Aβ are significantly changed, leading to increased levels of Aβ. When the autophagic Aβ degradation is defective in addition to the increased Aβ generation, the Aβ-regulation failure is accompanied by elevated concentrations of autophagosome and autolysosome, which may further clog neurons. CONCLUSIONS The model predicts that modulations of different steps of the autophagy pathway (i.e., Aβ sequestration, autophagosome maturation, and intralysosomal hydrolysis) have significant step-specific and combined effects on the Aβ levels and thus suggests therapeutic and preventive implications of autophagy in AD.

中文翻译：

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自噬对淀粉样β肽水平影响的计算模型。

背景自噬是一种进化上保守的细胞内过程，用于将蛋白质和细胞器递送至溶酶体进行降解。几十年来，人们推测自噬可以调节淀粉样β肽（Aβ）的积累，而这与阿尔茨海默病（AD）有关。然而，自噬对 Aβ 动力学的特定影响才刚刚开始被探索。结果我们开发了一个关于 Aβ 动力学的自噬数学模型，并进行模拟以了解 Aβ 水平和自噬活性之间的定量关系。在Aβ生成异常增加的情况下，Aβ的降解、分泌和清除率显着改变，导致Aβ水平升高。当自噬性 Aβ 降解除了 Aβ 生成增加之外还有缺陷时，Aβ 调节失败会伴随着自噬体和自溶酶体浓度升高，这可能会进一步阻塞神经元。结论 该模型预测自噬途径不同步骤（即 Aβ 隔离、自噬体成熟和溶酶体内水解）的调节对 Aβ 水平具有显着的步骤特异性和组合效应，因此表明自噬在 AD 中的治疗和预防意义。