Arbel-Ornath Michal, Hudry Eloise, Boivin Josiah R, Hashimoto Tadafumi, Takeda Shuko, Kuchibhotla Kishore V, Hou Steven, Lattarulo Carli R, Belcher Arianna M, Shakerdge Naomi, Trujillo Pariss B, Muzikansky Alona, Betensky Rebecca A, Hyman Bradley T, Bacskai Brian J
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA.
Department of Neuropathology, The University of Tokyo, Tokyo, Japan.
Mol Neurodegener. 2017 Mar 21;12(1):27. doi: 10.1186/s13024-017-0169-9.
Amyloid-β oligomers (oAβ) are thought to mediate neurotoxicity in Alzheimer's disease (AD), and previous studies in AD transgenic mice suggest that calcium dysregulation may contribute to these pathological effects. Even though AD mouse models remain a valuable resource to investigate amyloid neurotoxicity, the concomitant presence of soluble Aβ species, fibrillar Aβ, and fragments of amyloid precursor protein (APP) complicate the interpretation of the phenotypes.
To explore the specific contribution of soluble oligomeric Aβ (oAβ) to calcium dyshomeostasis and synaptic morphological changes, we acutely exposed the healthy mouse brain, at 3 to 6 months of age, to naturally occurring soluble oligomers and investigated their effect on calcium levels using in vivo multiphoton imaging.
We observed a dramatic increase in the levels of neuronal resting calcium, which was dependent upon extracellular calcium influx and activation of NMDA receptors. Ryanodine receptors, previously implicated in AD models, did not appear to be primarily involved using this experimental setting. We used the high resolution cortical volumes acquired in-vivo to measure the effect on synaptic densities and observed that, while spine density remained stable within the first hour of oAβ exposure, a significant decrease in the number of dendritic spines was observed 24 h post treatment, despite restoration of intraneuronal calcium levels at this time point.
These observations demonstrate a specific effect of oAβ on NMDA-mediated calcium influx, which triggers synaptic collapse in vivo. Moreover, this work leverages a method to quantitatively measure calcium concentration at the level of neuronal processes, cell bodies and single synaptic elements repeatedly and thus can be applicable to testing putative drugs and/or other intervention methodologies.
淀粉样β寡聚体（oAβ）被认为在阿尔茨海默病（AD）中介导神经毒性，先前对AD转基因小鼠的研究表明钙调节异常可能导致这些病理效应。尽管AD小鼠模型仍然是研究淀粉样神经毒性的宝贵资源，但可溶性Aβ物种、纤维状Aβ和淀粉样前体蛋白（APP）片段的同时存在使表型的解释变得复杂。
为了探究可溶性寡聚Aβ（oAβ）对钙稳态失衡和突触形态变化的具体作用，我们在3至6月龄的健康小鼠脑内急性暴露于天然存在的可溶性寡聚体，并使用体内多光子成像研究它们对钙水平的影响。
我们观察到神经元静息钙水平显著升高，这依赖于细胞外钙内流和NMDA受体的激活。在该实验环境中，先前在AD模型中涉及的兰尼碱受体似乎并非主要参与因素。我们使用体内获取的高分辨率皮质体积来测量对突触密度的影响，观察到虽然在oAβ暴露的第一小时内棘突密度保持稳定，但在处理后24小时观察到树突棘数量显著减少，尽管此时神经元内钙水平已恢复。
这些观察结果证明了oAβ对NMDA介导的钙内流具有特定作用，这在体内触发突触崩溃。此外，这项工作利用了一种方法来反复定量测量神经元突起、细胞体和单个突触元件水平的钙浓度，因此可适用于测试推定药物和/或其他干预方法。
