Liang Jingyi, Kulasiri Don, Samarasinghe Sandhya
Centre for Advanced Computational Solutions (C-fACS), Lincoln University, Christchurch, New Zealand.
PLoS One. 2017 Aug 24;12(8):e0182743. doi: 10.1371/journal.pone.0182743. eCollection 2017.
In Alzheimer's disease (AD), dysregulation of intracellular Ca2+ signalling has been observed as an early event prior to the presence of clinical symptoms and is believed to be a crucial factor contributing to AD pathogenesis. Amyloid-β oligomers (AβOs) disturb the N-methyl-D-aspartate receptor (NMDAR)-mediated postsynaptic Ca2+ signalling in response to presynaptic stimulation by increasing the availability of extracellular glutamate as well as directly disturbing the NMDARs. The abnormal Ca2+ response can further lead to impairments in long-term potentiation (LTP), an important process in memory formation. In this study, we develop a mathematical model of a CA1 pyramidal dendritic spine and conduct computational experiments. We use this model to mimic alterations by AβOs under AD conditions to investigate how they are involved in the Ca2+ dysregulation in the dendritic spine. The alterations in glutamate availability, as well as NMDAR availability and activity, are studied both individually and globally. The simulation results suggest that alterations in glutamate availability mostly affect the synaptic response and have limited effects on the extrasynaptic receptors. Moreover, overactivation of extrasynaptic NMDARs in AD is unlikely to be induced by presynaptic stimulation, but by upregulation of the resting level of glutamate, possibly resulting from these alterations. Furthermore, internalisation of synaptic NR2A-NMDAR shows greater damage to the postsynaptic Ca2+ response in comparison with the internalisation of NR2B-NMDARs; thus, the suggested neuroprotective role of the latter is very limited during synaptic transmission in AD. We integrate a CaMKII state transition model with the Ca2+ model to further study the effects of alterations of NMDARs in the CaMKII state transition, an important downstream event in the early phase of LTP. The model reveals that cooperation between NR2A- and NR2B-NMDAR is required for LTP induction. Under AD conditions, internalisation of membrane NMDARs is suggested to be the cause of the loss of synapse numbers by disrupting CaMKII-NMDAR formation.
在阿尔茨海默病（AD）中，细胞内钙离子信号失调被视为临床症状出现之前的早期事件，并且被认为是导致AD发病机制的关键因素。淀粉样β寡聚体（AβOs）通过增加细胞外谷氨酸的可用性以及直接干扰N-甲基-D-天冬氨酸受体（NMDAR），来扰乱NMDAR介导的突触后钙离子信号，以响应突触前刺激。异常的钙离子反应可进一步导致长时程增强（LTP）受损，而LTP是记忆形成中的一个重要过程。在本研究中，我们构建了一个CA1锥体树突棘的数学模型并进行了计算实验。我们使用该模型来模拟AD条件下AβOs引起的变化，以研究它们如何参与树突棘中的钙离子失调。分别单独和整体研究了谷氨酸可用性以及NMDAR可用性和活性的变化。模拟结果表明，谷氨酸可用性的变化主要影响突触反应，对突触外受体的影响有限。此外，AD中突触外NMDAR的过度激活不太可能由突触前刺激诱导，而是由谷氨酸静息水平的上调引起，这可能是由这些变化导致的。此外，与NR2B-NMDAR内化相比，突触NR2A-NMDAR的内化对突触后钙离子反应造成的损害更大；因此，在AD的突触传递过程中，后者所暗示的神经保护作用非常有限。我们将一个CaMKII状态转换模型与钙离子模型整合，以进一步研究NMDAR变化在CaMKII状态转换中的影响，CaMKII状态转换是LTP早期阶段的一个重要下游事件。该模型表明，LTP诱导需要NR2A-和NR2B-NMDAR之间的协同作用。在AD条件下，膜NMDAR的内化被认为是通过破坏CaMKII-NMDAR形成导致突触数量减少的原因。
