Olfactory deficit is associated with mitral cell dysfunction in the olfactory bulb of P301S tau transgenic mice
Olfactory deficit is associated with mitral cell dysfunction in the olfactory bulb of P301S tau transgenic mice
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嗅觉缺陷与 P301S tau 转基因小鼠嗅球二尖瓣细胞功能障碍有关
DOI：
10.1016/j.brainresbull.2019.03.006
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发表时间：
2019-05-01
影响因子：
3.8
通讯作者：
Ling, Shucai
中科院分区：
文献类型：
--
作者：
Li, Shanshan;Li, Weiyun;Ling, Shucai
由过度磷酸化的tau蛋白（P-tau）组成的神经元缠结是阿尔茨海默病（AD）的神经病理学标志，嗅觉障碍是AD的早期症状。然而，P-tau聚集和嗅觉障碍之间的联系仍然不清楚。在本研究中，发现P-tau在AD患者嗅球（OB），特别是在僧帽细胞层（MCL）、外网状层（EPL）和颗粒细胞层（GCL）中的表达显著高于正常衰老受试者的OB，这表明OB中的这些层对P-tau敏感。P301 S tau转基因小鼠（P301 S小鼠）表现出AD样特征，其特征在于认知障碍之前的嗅觉功能障碍。重要的是，P301 S小鼠OB，特别是MC中P-tau的过度表达与9月龄时的MC损失相关，并且在2月龄时开始观察到MC放电活动减少。我们的研究结果表明，MCs可能有助于P301 S小鼠的嗅觉功能障碍。此外，我们描述了一个异常的树突-树突状突触结构之间的颗粒细胞（GC）和MC和异常的γ振荡的EPL的OB，这些研究结果表明，P-tau可能会破坏的GC在P301 S小鼠从5个月大的MC的调节。这些数据表明，MC放电频率在2月龄的减少可能不是由GC抑制引起的。基于这些发现，我们推测MC是治疗P-tau诱导的早期嗅觉功能障碍的假定靶点，因此，探索P301 S小鼠MC功能变化的具体原因和机制至关重要。
Neurofibrillary tangles consisting of hyperphosphorylated tau (P-tau) are the neuropathological hallmark of Alzheimer's disease (AD), and olfaction disorder is an early symptom of AD. However, the link between P-tau aggregation and olfaction disorder remains unclear. In this study, the expression of P-tau in the olfactory bulb (OB), particularly in the mitral cell layer (MCL), external plexiform layer (EPL), and granule cell layer (GCL), of AD patients was found to be significantly higher than that in the OB of normal aging subjects, which suggested that these layers in the OB were susceptible to P-tau. The P301S tau transgenic mice (P301S mice) exhibit AD-like features, which can be characterized by olfactory dysfunction that precedes cognitive disorder. Importantly, the excessive P-tau expression in the OB of P301S mice, particularly in MCs, was associated with MC loss at 9 months of age, and decreased MC firing activities started to be observed at 2 months of age. Our results revealed that MCs might contribute to olfactory dysfunction in P301S mice. Furthermore, we described an aberrant dendro-dendritic synaptic structure between granule cells (GCs) and MCs and abnormal gamma oscillations in the EPL of the OB, and these findings indicated that P-tau might disrupt the regulation of MCs by GCs in P301S mice starting at 5 months of age. These data showed that the reduction in the MC firing frequency at 2 months of age might not be caused by GC suppression. Based on these findings, we speculated that MCs are a putative target for the treatment of P-tau-induced early olfactory dysfunction, and thus, an exploration of the specific causes and mechanisms of MC functional changes in P301S mice is crucial.