Institute of Neuroscience and Anatomy, School of Medicine, Zhejiang University, Hangzhou, China.
Institute of Neuroscience and Anatomy, School of Medicine, Zhejiang University, Hangzhou, China; Department of Clinical Medicine, Zhejiang University City College, Hangzhou, China.
Brain Res Bull. 2019 May;148:34-45. doi: 10.1016/j.brainresbull.2019.03.006. Epub 2019 Mar 19.
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.
神经原纤维缠结由过度磷酸化的 tau（P-tau）组成，是阿尔茨海默病（AD）的病理标志，而嗅觉障碍是 AD 的早期症状。然而，P-tau 聚集与嗅觉障碍之间的联系尚不清楚。在这项研究中，发现 AD 患者的嗅球（OB）中 P-tau 的表达，特别是在僧帽细胞层（MCL）、外丛状层（EPL）和颗粒细胞层（GCL）中的表达明显高于正常衰老受试者的 OB，这表明 OB 的这些层容易受到 P-tau 的影响。P301S tau 转基因小鼠（P301S 小鼠）表现出 AD 样特征，其特征是嗅觉功能障碍先于认知障碍。重要的是，P301S 小鼠 OB 中 P-tau 的过度表达，特别是在 MC 中，与 9 个月龄时的 MC 丢失有关，并且在 2 个月龄时就开始观察到 MC 放电活动减少。我们的结果表明，MC 可能导致 P301S 小鼠的嗅觉功能障碍。此外，我们描述了 OB 中颗粒细胞（GC）和 MC 之间的异常树突-树突突触结构和 EPL 中的异常γ振荡，这些发现表明，从 5 个月龄开始，P-tau 可能破坏 P301S 小鼠中 GC 对 MC 的调节。这些数据表明，2 个月龄时 MC 放电频率的降低可能不是由 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潜在靶点，因此，探索 P301S 小鼠 MC 功能变化的具体原因和机制至关重要。
