Progressive effect of beta amyloid peptides accumulation on CA1 pyramidal neurons: a model study suggesting possible treatments
Progressive effect of beta amyloid peptides accumulation on CA1 pyramidal neurons: a model study suggesting possible treatments
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DOI：
10.3389/fncom.2012.00052
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发表时间：
2012-07-23
影响因子：
3.2
通讯作者：
Migliore, Michele
中科院分区：
文献类型：
--
作者：
Culmone, Viviana;Migliore, Michele
几项独立的研究表明，β-淀粉样蛋白（A β）肽的积累，阿尔茨海默病（AD）的特征之一，可以以不同的方式影响正常的神经元活动。然而，尽管紧张的实验工作，以解释可能的潜在机制的行动，一个全面和一致的理解仍然缺乏。部分问题可能是实验发现A β影响神经元正常活动的相反方式;例如，使神经元更易兴奋（通过减少A-或DR-型K+电流）或减少兴奋（通过减少突触传递和Na+电流）。因此，总体情况令人困惑，因为许多机制的相互作用使得很难将个别实验结果与理解疾病进展的更普遍问题联系起来。这是一个重要的问题，特别是对于试图改善疾病影响的新药的开发。我们通过计算模型解决了这些矛盾。我们首先通过逐步修改现实模型神经元的固有膜和突触特性来模拟AD的不同阶段，同时考虑多个不同的实验结果，并通过评估每个机制对细胞兴奋性的整体调节的贡献。然后，我们测试了一些操纵通道和突触激活特性，可以补偿A β的影响。该模型预测了可能的治疗方法的药理学操纵通道的动力学和激活特性。研究结果还表明，药物如何以及哪些机制可以靶向恢复原始的放电条件。
Several independent studies show that accumulation of beta-amyloid(A beta) peptides, one of the characteristic hallmark of Alzheimer's Disease (AD), can affect normal neuronal activity in different ways. However, inspite of intense experimental work to explain the possible underlying mechanisms of action, a comprehensive and congruent understanding is still lacking. Part of the problem might be the opposite ways in which A beta have been experimentally found to affect the normal activity of a neuron; for example, making a neuron more excitable (by reducing the A- or DR-type K+ currents) or less excitable (by reducing synaptic transmission and Na+ current). The overall picture is therefore confusing, since the interplay of many mechanisms makes it difficult to link individual experimental findings with the more general problem of understanding the progression of the disease. This is an important issue, especially for the development of new drugs trying to ameliorate the effects of the disease. We addressed these paradoxes through computational models. We first modeled the different stages of AD by progressively modifying the intrinsic membrane and synaptic properties of a realistic model neuron, while accounting for multiple and different experimental findings and by evaluating the contribution of each mechanism to the overall modulation of the cell's excitability. We then tested a number of manipulations of channel and synaptic activation properties that could compensate for the effects of A beta. The model predicts possible therapeutic treatments in terms of pharmacological manipulations of channels' kinetic and activation properties. The results also suggest how and which mechanisms can be targeted by a drug to restore the original firing conditions.